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Conservation of the three-dimensional structure in non-homologous or unrelated proteins

Abstract

In this review, we examine examples of conservation of protein structural motifs in unrelated or non-homologous proteins. For this, we have selected three DNA-binding motifs: the histone fold, the helix-turn-helix motif, and the zinc finger, as well as the globin-like fold. We show that indeed similar structures exist in unrelated proteins, strengthening the concept that three-dimensional conservation might be more important than the primary amino acid sequence.

Introduction

When the human genome was sequenced (as well as that of other mammals), it was estimated that there are approximately 25,000 genes encoding for proteins [1, 2]. After being synthesized, proteins assume their three-dimensional structure by a specific arrangement of beta strands, alpha helices, turns, or loops. In many cases, a combination of these structural features creates certain motifs, exerting a particular function (i.e., DNA binding) that is quite conserved in proteins from virtually all organisms. Interestingly, the number of these motifs is much smaller than the number of genes. However, it has also been noted that some structural motifs show significant robustness even though no significant homology exists among them at the primary amino acid sequence. It seems that evolutionary constraints have limited the ability of proteins to become vastly different. Moreover, it has been shown that protein structures are three to ten times more conserved than the amino acid sequence [3]. Thus, a particular motif, i.e., a zinc-binding domain of very similar or virtually identical structure, can be found in many different proteins, which could also be unrelated to each other when function is concerned. Thus, it seems that evolution does favor conservation of structural motifs in proteins.

The purpose of this tutorial/review is to illustrate this diversity that exists in the function of structurally conserved protein motifs. For this reason, protein folds with low homology in amino acid sequence and high structural similarity were used. The analysis for the obvious reason of space is not exhaustive and is focused on four specific protein structural folds: We have selected to present data with three different DNA-binding domains: the histone fold, the helix-turn-helix motif (HTH), and the zinc finger, as well the globin-like fold, part of an important protein in oxygen binding and transport. These four folds were chosen because they are ubiquitous in many different organisms and are well represented in many different proteins.

For our comparisons, an intensive search of the Vector Alignment Search Tool (VAST) [4, 5], an algorithm to determine three-dimensional (3D) structure similarities according to geometric criteria, was done. A protein family was identified using a representative protein and, using VAST and the Molecular Modeling Database [6], dissimilar structure proteins were identified and annotated followed by root mean square deviation (RMSD) determination. The structures were then downloaded into Cn3D (‘see in 3D’) [7] for viewing the sequence alignment. The above are part of Entrez [8, 9]. These structures were then aligned in PyMOL [10] for 3D viewing. The files for the PyMOL structures provided have been downloaded from the Protein Data Bank (PDB) [11]. The lower the RMSD means better structural alignment. Lower identity means that the two proteins do not share the same amino acids in the corresponding structural alignment. Though, depending on how big are the structures that we are comparing, the RMSD and sequence identity may vary. Small domains may contain always certain amino acids increasing the identity. On the other hand, big proteins may not align well and may increase the RMSD. For the present analysis, we chose to set the limits as follows: RMSD to be lower than 3.5 and amino acid identity to be lower than 25% in order to conclude that this pair of proteins has similar structures but dissimilar sequences.

Globin-like fold

Globin-like fold is an all-alpha protein fold normally consisting of six alpha helices [12]. The number of helices can be altered in different families of globin-like proteins. These helices are not randomly distributed in the protein, but they are oriented following standard helix-helix packing rules in order to form a globular structure. Globin-like fold is mostly known from hemoglobins (Figure 1) and myoglobins which play an important role in transferring oxygen to all the tissues of an organism with the help of heme groups which can bind oxygen reversibly. The heme-binding proteins are part of the actual family of globins [12].

Figure 1
figure 1

Human hemoglobin (PDB: 2DN2; chain A) [13].

The globin family was the first example that showed structural conservation even in different organisms [14–17] and led scientists' pursuit to prove that 3D structures of proteins are more conserved than their sequences. It turned out that globin-like folds exist in many proteins with different functions. Hemoglobins and myoglobins play a role in oxygen transport; cyanoglobins [18] bind to oxygen to help in cellular processes; phycocyanins and phycoerythrins [19, 20] play a role in absorbing light; cytokines and immuno-globins [21, 22] play a role in the immune system; and fibronectin [23] is part of the extracellular matrix. Natural selection kept the 3D structure of this fold intact [24] while utilizing it for different functions to meet other required organismal requirements.

We have compared pairs of functionally different proteins or proteins from organisms that diversified long ago. Figure 2 shows the 3D structural conservation despite low sequence similarity. structure is conserved in a monomeric hemoglobin of a trematode (PDB: 1H97) compared to a hemoglobin which is part of a large protein (3.6 million Da) from an annelid (PDB: 2GTL). In this case, the single hemoglobin from a trematode can bind and transport oxygen. However, it is structurally relevant to hemoglobins that are part of a 3.6 million-Da protein, an erythrocruorin, which serves the same purpose but has more advantages such as resistance to oxidation and other cooperative binding properties [25, 26]. Both proteins are part of the globin-like superfamily [12].

Figure 2
figure 2

Comparison of structure and sequence similarity of sample globin-like fold proteins according to PDB number. First column: PDB number and a brief description of the protein. Second column: RMSD and amino acid sequence identity as defined by VAST. Third column: Left is the alignment of the two proteins taken by PyMOL. In the structure representation, the first protein is in pink, and the second, in cyan. Right is the alignment of the two proteins taken by Cn3D. In the sequence representation, red indicates the same amino acid, whereas yellow indicates differing amino acids. Fourth column: references.

In the next example, structural conservation of a plant hemoglobin (PDB: 2GNW), which may play a role in binding free molecules that cause oxidation, and a globin-coupled sensor (PDB: 2W31), which plays a role in adapting the organism in the presence of oxygen via transmitted signals to a transmembrane protein, can be seen [27, 28]. This example demonstrates how a globin-like fold has been used for different kinds of responses from scavenging hazardous active molecules to sense external stimuli and cooperate with other proteins to get the appropriate response. Both proteins are part of the globin-like superfamily [12].

Nitric oxide detoxification in M. tuberculosis occurs with the help of a truncated hemoglobin protein (PDB: 2GLN). Its structure is similar to an extracellular giant hemoglobin from an annelid (PDB: 2ZS1) that plays a role in binding oxygen [29, 30].

Certain organisms absorb light through pigments. Allophycocyanin is a pigment and its structure is part of the phycobilisome family [12]. This structure (PDB: 1KN1) is similar to a protein that plays a role in regulating the sigma (s) factor during transcription (PDB: 2BNL) and belongs to the Rsbr_N superfamily (VAST) [31, 32]. This is an example of using the globin-like fold as a building block to make a larger structure like the N-domain of the rsbr to serve a different role.

The last example is from two organisms that evolved separately for many millions of years: a neuroglobin (PDB: 1OJ6) from Homo sapiens and a protoglobin (PDB: 2VEB) from archaea. The role of globin-like proteins in archaea is not yet fully determined. It is proposed to play a role in metabolism of the strictly anaerobic M. acetivorans and to be the building block of globin-coupled sensors. The structure is similar to the neuroglobin from humans which play an important role in regulating oxygen transport in neural tissues [33, 34].

Histone fold

This motif is most commonly associated with histones but can also be found in a multitude of proteins such as DNA-binding transcription initiation factors which are functionally conserved in archaea and eukaryotes [35]. Because of this functional conservation in archaea and eukaryotes, the histone fold is thought to be an ancient motif [36]. Interestingly, the pure functionality of the histone fold is not found in eubacteria [37]. As seen in Figure 3, the basic structure of the histone fold comprises a central alpha helix flanked on each side by two smaller helices.

Figure 3
figure 3

The typical histone fold. It consists of one central helix flanked on each side by a shorter alpha helix (PDB: 1HTA) [38].

Due to the hydrophobic nature of the histone fold, it is only stable within histone fold-to-histone fold dimers. Eukaryotic histones, for example, dimerize specifically with H2A dimerizing with H2B and H3 dimerizing with H4, thereby creating the basis of the histone octamer. Archaea histones appear to have less specificity in dimerizing to a specific partner but, through dimerization, utilize the histone fold to produce a similar histone structure [38, 39].

Since the function of histones and the histone fold are shared by archaea and eukarya, it is thought to have been derived from an early thermophile which initially utilized the histone fold to maintain the integrity of DNA under thermal stress. This increased integrity would have also brought about the added benefit of genome compaction which would have required a mechanism to unwind and transcribe those genes and thus the appearance of proteins such as TATA box-binding proteins and transcription initiation factors which also utilize the histone fold and are functionally conserved in both eukaryotic and archaea organisms [35, 40, 41]. Since the packaging and protection of DNA is paramount along with the ability to transcribe DNA when needed, the numerous essential interactions have caused the histone fold to be conserved [42].

From a molecular point of view, the histone fold is thought to have evolved from the helix-strand-helix (HSH) motif where duplication caused two helices to merge, forming a larger central helix [36, 43]. Alva et al. demonstrated how this could occur by shortening the HSH strand which led to a 3D swap and caused the dimerization of two HSH motifs. This dimerization recovered the interactions between the HSH motifs due to the strand shortening and thereby causing the histone fold [43].

As mentioned previously, eubacteria do not appear to contain the histone fold motif. They do, however, contain proteins which have histone-like proteins. The most ubiquitous of these proteins is the HU protein (H for histone-like and U from the U93 strain of Escherichia coli, in which it was identified from). HU proteins are essential in maintaining the nucleoid structure and are involved in all DNA-dependent functions [44]. Interestingly, the HSH-type motif is found in HU proteins of eubacteria which also have histone-like functionality [42, 45]. Looking at the structures of HU and the histone fold (Figure 4), one can easily identify similarities in the HSH with respect to the histone fold, thereby showing how the functionality of DNA binding has been conserved through different but similar means.

Figure 4
figure 4

Comparison of the histone fold (PDB: 1HTA)[38]to eubacteria HU protein (PDB: 1MUL)[46]. Hot pink: histone fold, cyan: eubacteria HU protein. Notice the similarity in the helix-turn-helix and the size difference in the central helix.

Interestingly, some proteins have evolved a method to overcome the need of the dimerization of different proteins through a double histone fold. A double histone fold is essentially two histone folds occurring in a single peptide chain which can ‘dimerize’ with itself [47]. As seen in Figure 5, a great structural similarity between the H2A/H2B two-protein dimer has a great structural similarity to the single-protein Son of sevenless (Sos) protein [48, 49]. With the double histone fold being so ‘economical’ by not needing to dimerize with another protein, it is not surprising that it was recently found in a virus where it is hypothesized to aid in the packaging and organization of DNA inside the capsid [50].

Figure 5
figure 5

Comparison of structure and sequence similarity of sample histone fold proteins according to PDB number. First column: PDB number and a brief description of the protein. Second column: RMSD and amino acid sequence identity as defined by VAST. Third column: Left is the alignment of the two proteins taken by PyMOL. In the structure representation, the first protein is in pink, and the second, in cyan. Right is the alignment of the two proteins taken by Cn3D. In the sequence representation, red indicates the same amino acid, whereas yellow indicates differing amino acids. Fourth column: references.

Due to the multiple interactions required of the histone fold, the selective pressures limit a large differentiation in sequence identity. For example, H3 and H4 histones are among the most highly conserved proteins in terms of sequence and length due to their specific interactions with DNA. H2A and H2B have regions which show greater variability but show great specificity to dimerizing with each other. Despite the conservation of the histone fold in the histone structure, these four core eukaryotic histones have little sequence similarity (15–20%) with one another [42]. Interestingly, even proteins such as the histone H2A/H2B and the cytoplasmic hSos [50] (Figure 5, example 4) which show strong structural similarity but do not seem to function as histones or DNA-binding factors still do not stray far from this sequence identity. This sequence similarity is seen in organisms which are obviously so evolutionary distant as archaea and eukaryotes [51, 52] (Figure 5, examples 1 and 2). This may be due to the hydrophobic residue interactions required in all six helices of a histone fold dimer [39].

Helix-turn-helix motif

HTH motif consists of an α-helix, a turn, and a second α-helix which is often called the ‘recognition’ helix as the part of the HTH motif that fits into the DNA major groove. There are several positions significant to keep the HTH structure rather than to specify contacts with the DNA, while the amino acid residues in other positions are usually varied to determine the specificity of DNA-protein interactions [53]. This motif is found in many DNA-binding domains and transcriptional factors such as homeotic proteins. This sequence, which is conserved in many organisms for related proteins, was used to discover a large number of DNA-binding proteins [54]

Winged helix-turn-helix (wHTH, Figure 6) shares the same original ancestor as that of HTH in evolutionary history; it is also a DNA-binding domain which binds to specific DNA sequences. The wHTH is formed by a three-helix bundle (α1, α2, α3) and a three- or four-strand beta-sheet. The α2 and α3 helices are similar to those of the HTH motif except that wHTH has beta-sheet wings on the ends of HTH parts. Many repressor DNA-binding domains like LexA, arginine, Rex, ArsR, and MarR form a wHTH structure.

Figure 6
figure 6

A typical winged helix-turn-helix structure (PDB: 3JSO) [55].

Figure 7 shows five examples of HTH comparisons of different proteins. All of them show high structural similarity and low sequence identity. In addition, the examples compare HTH motifs from different organisms that do different functions.

Figure 7
figure 7

Comparison of structure and sequence similarity of sample helix-turn-helix motif proteins according to PDB number. First column: PDB number and a brief description of the protein. Second column: RMSD and amino acid sequence identity as defined by VAST. Third column: Left is the alignment of the two proteins taken by PyMOL. In the structure representation, the first protein is in pink, and the second, in cyan. Right is the alignment of the two proteins taken by Cn3D. In the sequence representation, red indicates the same amino acid, whereas yellow indicates differing amino acids. Fourth column: references.

An ancestral archaea homolog of the N-terminal of the transcription factor II E subunit a (PDB: 1Q1H) [56] folds as a wHTH. This domain has a groove which is negatively charged. Thus, it cannot bind to negatively charged DNA as in vitro experiments show. Though, it promotes interactions with other proteins. This domain has structural similarities with a catabolite gene activator protein (PDB: 1RUN) [57], a protein that is known to bind DNA. This example clearly illustrates that natural selection chose structures to have different roles than the dominant ones. Cro repressor from the λ phage (PDB: 1D1L) [58] forms a dimer by two antiparallel b-strands in order to bind to DNA. This protein has structural similarities with the bacterial Fis protein (PDB: 3JRH) [59] which binds to DNA with no sequence specificity.

Transcriptional regulators can be triggered to function by different signals from the environment. Signals that are not related with signal transduction cascades, which involve primarily phosphorylation or dephosphorylation of proteins, can involve smaller molecules like metals or oxygen. This is the case for SmtB (1R1T) [60], a cyanobacterial repressor protein that has reduced affinity for DNA in the presence of metals. The HTH motif of this repressor is structurally similar to the HTH motif of the bacterial DosR protein (PDB: 1ZLK) [61] which prolongs survival when the organism is left without oxygen.

OhrR is a bacterial protein (PDB: 1Z9C) [62] that has a HTH motif composed of eukaryotic-like wHTH, prokaryotic HTH motifs, and other helices. This protein is induced to function by oxidation of certain residues. This chimeric HTH motif is structurally similar to the HTH motif of a DNA-binding domain of a γδ resolvase in E. coli (PDB: 1RES) [63].

Finally, the HTH motif from a bacterial transcriptional regulator, AraC-type (PDB: 3OIO), is structurally similar to that of the transcriptional activator MarA (PDB: 1XS9) [64] which is associated with the RNA polymerase and binds to DNA as a monomer.

Zinc finger motif

Zinc (Zn) fingers (see Figure 8) are small structural motifs whose structure is stabilized by a zinc ion, and they are the most common DNA- or RNA-binding motif in different proteins. There are different structural types of Zn fingers and are present in proteins that perform a broad array of functions such as replication and repair, transcription and translation, metabolism and signaling, cell proliferation, and apoptosis [65]. Zn fingers occupy 3% of the genes in the human genome [66]. The major part of structural stability of Zn fingers is provided by zinc coordination and by the conserved hydrophobic core that flanks the Zn binding site. There are a relatively small number of conserved residues present in Zn fingers [67].

Figure 8
figure 8

Structure of C2H2 zinc finger of transcription factor IIIA of Xenopus laevis (PDB: 2HGH,[68]). (A) Cartoon representation with zinc as a ball. (B) Includes the two cysteines and two histidines that interact with the zinc as sticks.

Classical Cys2-His2 (C2H2) Zn fingers have about 30 amino acids in which 25 of the 30 amino acid residues form a loop around the central Zn ion and the 5 other amino acids form the linkers between the consecutive Zn fingers. It consists of two secondary structural units: The first one is an antiparallel beta-sheet, which contains the loop formed by the two cysteines, and the second one is an alpha helix containing the His-His. These two structural units are held together by the zinc atom. The Zn ion tetrahedrally coordinates to the conserved pairs of cysteines and histidines, and this coordination is vital for the maintenance of the overall structure of the Zn finger. The majority of the 30 amino acids are polar and basic residues which are important in nucleic acid binding. In addition to the conserved cysteines and histidines which are vital for the formation of the Zn finger fold, there are other conserved amino acids, notably Tyr, Phe, and Leu, which form a hydrophobic structural core of the folded structure [66].

In the example shown in Figure 9, each pair of the compared Zn fingers have less sequence similarity, sometimes bind to different types of molecules, may have different functions, may belong to different species, but exhibit a great structural overlap. This supports the notion that only few small numbers of conserved residues are required for the maintenance of the overall structure of the zinc finger.

Figure 9
figure 9

Comparison of structure and sequence similarity of sample zinc finger motif proteins according to PDB number. First column: PDB number and a brief description of the protein. Second column: RMSD and amino acid sequence identity as defined by VAST. Third column: Left is the alignment of the two proteins taken by PyMOL. In the structure representation, the first protein is in pink, and the second, in cyan. Right is the alignment of the two proteins taken by Cn3D. In the sequence representation, red indicates the same amino acid, whereas yellow indicates differing amino acids. Fourth column: references.

Example 1 in Figure 9 shows two DNA-binding proteins: a DNA-binding domain (DBD) from the GAGA factor (PDB: 1YUJ) [69] and one of the zinc finger domains from zinc finger protein 692 (PDB: 2D9H), which belong to D. melanogaster and H. sapiens, respectively. The DBD of the GAGA factor uses only one zinc finger in contrast to other zinc finger proteins which commonly use more than two in order to have a good affinity for the DNA. They show a great structural similarity despite low sequence identity.

The hydroxylase domain from methane monooxygenase (PDB: 1MHZ) [70] contains a Zn finger which does not bind to DNA. Though, it is structurally very similar (RMSD: 1.5) and their sequence is very different (3%) from the human Zn finger 2 which binds to DNA (PDB: 3ODC) [71]. This is a good example to point out that structures are built up from extensively used raw materials (domains) like the Zn finger even if they are not going to be used as the majority of the other proteins in which these domains are found.

In the third example, and as a follow up from the previous one, the two proteins are monooxygenases (PDB: 1MHZ, 2INC) [70, 72] which belong to different species and have Zn finger domains whose structures overlap.

YY1 (PDB: 1UBD) [73] is a protein with four Zn fingers and is structurally similar to kruppel-like factor 3 (PDB: 1U85), which contains a Zn finger with tryptophan as shown in the fourth example.

Finally, the Zn finger in U11/U12 (PDB: 2VY4) [74], which is a RNA-binding protein, has a good structural overlap with SAGA protein (PDB: 3MHH) [75], which is a DNA-binding protein, in spite of the low sequence similarity. In addition, the role of SAGA is to deubiquitinate H2B histone, so the affinity for DNA helps to dock to the nucleosome. This example was selected because these two different proteins bind to two different types of nucleic acids, have different functions, have low sequence identity, but exhibit a good overall structural similarity.

Concluding remarks

In this review, we have selected four protein motifs, which are present in several DNA-binding proteins and in oxygen-carrying and -transporting proteins. Using several comparisons, we show that these motifs exhibit an astonishing degree of structural conservation even though their primary sequence is not similar and even when they are involved in different functions. The examples underscore the importance of structure selection in evolution and a strategy of economy that nature is implementing. Much is to be learned when similar structures have evolved despite unrelated function. It will be interesting to determine how such similar structures have evolved and what could the possible ancestors be. Eventually, when all structures have been solved, evolution of protein structure will provide valuable information on protein function in general.

References

  1. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, et al: Initial sequencing and analysis of the human genome. Nature. 2001, 409: 860-921. 10.1038/35057062.

    Article  CAS  PubMed  Google Scholar 

  2. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, et al: The sequence of the human genome. Science. 2001, 291: 1304-1351. 10.1126/science.1058040.

    Article  CAS  PubMed  Google Scholar 

  3. Illergard K, Ardell DH, Elofsson A: Structure is three to ten times more conserved than sequence–a study of structural response in protein cores. Proteins. 2009, 77: 499-508. 10.1002/prot.22458.

    Article  CAS  PubMed  Google Scholar 

  4. Gibrat JF, Madej T, Bryant SH: Surprising similarities in structure comparison. Curr Opin Struct Biol. 1996, 6: 377-385. 10.1016/S0959-440X(96)80058-3.

    Article  CAS  PubMed  Google Scholar 

  5. Madej T, Gibrat JF, Bryant SH: Threading a database of protein cores. Proteins. 1995, 23: 356-369. 10.1002/prot.340230309.

    Article  CAS  PubMed  Google Scholar 

  6. Ohkawa H, Ostell J: Bryant S. MMDB: an ASN.1 specification for macromolecular structure. Proc Int Conf Intell Syst Mol Biol. 1995, 3: 259-267.

    CAS  PubMed  Google Scholar 

  7. Hogue CW: Cn3D: a new generation of three-dimensional molecular structure viewer. Trends Biochem Sci. 1997, 22: 314-316. 10.1016/S0968-0004(97)01093-1.

    Article  CAS  PubMed  Google Scholar 

  8. Hogue CW, Ohkawa H, Bryant SH: A dynamic look at structures: WWW-Entrez and the Molecular Modeling Database. Trends Biochem Sci. 1996, 21: 226-229.

    Article  CAS  PubMed  Google Scholar 

  9. Schuler GD, Epstein JA, Ohkawa H, Kans JA: Entrez: molecular biology database and retrieval system. Methods Enzymol. 1996, 266: 141-162.

    Article  CAS  PubMed  Google Scholar 

  10. Schrodinger LLC: The PyMOL Molecular Graphics System. 2006, Version, 99-

    Google Scholar 

  11. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000, 28: 235-242. 10.1093/nar/28.1.235.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Murzin AG, Brenner SE, Hubbard T, Chothia C: SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol. 1995, 247: 536-540.

    CAS  PubMed  Google Scholar 

  13. Park SY, Yokoyama T, Shibayama N, Shiro Y, Tame JR: 1.25 A resolution crystal structures of human haemoglobin in the oxy, deoxy and carbonmonoxy forms. J Mol Biol. 2006, 360: 690-701. 10.1016/j.jmb.2006.05.036.

    Article  CAS  PubMed  Google Scholar 

  14. Kendrew JC, Bodo G, Dintzis HM, Parrish RG, Wyckoff H, Phillips DC: A three-dimensional model of the myoglobin molecule obtained by x-ray analysis. Nature. 1958, 181: 662-666. 10.1038/181662a0.

    Article  CAS  PubMed  Google Scholar 

  15. Kendrew JC, Dickerson RE, Strandberg BE, Hart RG, Davies DR, Phillips DC, Shore VC: Structure of myoglobin: a three-dimensional Fourier synthesis at 2 A. resolution. Nature. 1960, 185: 422-427. 10.1038/185422a0.

    Article  CAS  PubMed  Google Scholar 

  16. Perutz MF, Muirhead H, Cox JM, Goaman LC: Three-dimensional Fourier synthesis of horse oxyhaemoglobin at 2.8 A resolution: the atomic model. Nature. 1968, 219: 131-139. 10.1038/219131a0.

    Article  CAS  PubMed  Google Scholar 

  17. Perutz MF, Rossmann MG, Cullis AF, Muirhead H, Will G, North AC: Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis. Nature. 1960, 185: 416-422. 10.1038/185416a0.

    Article  CAS  PubMed  Google Scholar 

  18. Trent JT: Kundu S, Hoy JA, Hargrove MS: Crystallographic analysis of synechocystis cyanoglobin reveals the structural changes accompanying ligand binding in a hexacoordinate hemoglobin. J Mol Biol. 2004, 341: 1097-1108. 10.1016/j.jmb.2004.05.070.

    Article  CAS  PubMed  Google Scholar 

  19. Ficner R, Lobeck K, Schmidt G: Huber R. Isolation, crystallization, crystal structure analysis and refinement of B-phycoerythrin from the red alga Porphyridium sordidum at 2.2 A resolution. J Mol Biol. 1992, 228: 935-950.

    CAS  PubMed  Google Scholar 

  20. Schirmer T, Bode W, Huber R, Sidler W, Zuber H: X-ray crystallographic structure of the light-harvesting biliprotein C-phycocyanin from the thermophilic cyanobacterium Mastigocladus laminosus and its resemblance to globin structures. J Mol Biol. 1985, 184: 257-277. 10.1016/0022-2836(85)90379-1.

    Article  CAS  PubMed  Google Scholar 

  21. Rozwarski DA, Gronenborn AM, Clore GM, Bazan JF, Bohm A, Wlodawer A, Hatada M, Karplus PA: Structural comparisons among the short-chain helical cytokines. Structure. 1994, 2: 159-173. 10.1016/S0969-2126(00)00018-6.

    Article  CAS  PubMed  Google Scholar 

  22. Williams AF, Barclay AN: The immunoglobulin superfamily–domains for cell surface recognition. Annu Rev Immunol. 1988, 6: 381-405. 10.1146/annurev.iy.06.040188.002121.

    Article  CAS  PubMed  Google Scholar 

  23. Bork P, Doolittle RF: Proposed acquisition of an animal protein domain by bacteria. Proc Natl Acad Sci USA. 1992, 89: 8990-8994. 10.1073/pnas.89.19.8990.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Aronson HE, Royer WE: Hendrickson WA: Quantification of tertiary structural conservation despite primary sequence drift in the globin fold. Protein Sci. 1994, 3: 1706-1711. 10.1002/pro.5560031009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Pesce A, Dewilde S, Kiger L, Milani M, Ascenzi P, Marden MC, Van Hauwaert ML, Vanfleteren J, Moens L, Bolognesi M: Very high resolution structure of a trematode hemoglobin displaying a TyrB10-TyrE7 heme distal residue pair and high oxygen affinity. J Mol Biol. 2001, 309: 1153-1164. 10.1006/jmbi.2001.4731.

    Article  CAS  PubMed  Google Scholar 

  26. Royer WE: Sharma H, Strand K, Knapp JE, Bhyravbhatla B: Lumbricus erythrocruorin at 3.5 A resolution: architecture of a megadalton respiratory complex. Structure. 2006, 14: 1167-1177. 10.1016/j.str.2006.05.011.

    Article  CAS  PubMed  Google Scholar 

  27. Pesce A, Thijs L, Nardini M, Desmet F, Sisinni L, Gourlay L, Bolli A, Coletta M, Van Doorslaer S, Wan X, Alam M, Ascenzi P, Moens L, Bolognesi M, Dewilde S: HisE11 and HisF8 provide bis-histidyl heme hexa-coordination in the globin domain of Geobacter sulfurreducens globin-coupled sensor. J Mol Biol. 2009, 386: 246-260. 10.1016/j.jmb.2008.12.023.

    Article  CAS  PubMed  Google Scholar 

  28. Smagghe BJ, Kundu S, Hoy JA, Halder P, Weiland TR, Savage A, Venugopal A, Goodman M, Premer S, Hargrove MS: Role of phenylalanine B10 in plant nonsymbiotic hemoglobins. Biochemistry. 2006, 45: 9735-9745. 10.1021/bi060716s.

    Article  CAS  PubMed  Google Scholar 

  29. Numoto N, Nakagawa T, Kita A, Sasayama Y, Fukumori Y, Miki K: Structural basis for the heterotropic and homotropic interactions of invertebrate giant hemoglobin. Biochemistry. 2008, 47: 11231-11238. 10.1021/bi8012609.

    Article  CAS  PubMed  Google Scholar 

  30. Ouellet Y, Milani M, Couture M, Bolognesi M, Guertin M: Ligand interactions in the distal heme pocket of Mycobacterium tuberculosis truncated hemoglobin N: roles of TyrB10 and GlnE11 residues. Biochemistry. 2006, 45: 8770-8781. 10.1021/bi060112o.

    Article  CAS  PubMed  Google Scholar 

  31. Liu JY, Jiang T, Zhang JP, Liang DC: Crystal structure of allophycocyanin from red algae Porphyra yezoensis at 2.2-A resolution. J Biol Chem. 1999, 274: 16945-16952. 10.1074/jbc.274.24.16945.

    Article  CAS  PubMed  Google Scholar 

  32. Murray JW, Delumeau O, Lewis RJ: Structure of a nonheme globin in environmental stress signaling. Proc Natl Acad Sci USA. 2005, 102: 17320-17325. 10.1073/pnas.0506599102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Nardini M, Pesce A, Thijs L, Saito JA, Dewilde S, Alam M, Ascenzi P, Coletta M, Ciaccio C, Moens L, Bolognesi M: Archaeal protoglobin structure indicates new ligand diffusion paths and modulation of haem-reactivity. EMBO Rep. 2008, 9: 157-163. 10.1038/sj.embor.7401153.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Pesce A, Dewilde S, Nardini M, Moens L, Ascenzi P, Hankeln T, Burmester T, Bolognesi M: Human brain neuroglobin structure reveals a distinct mode of controlling oxygen affinity. Structure. 2003, 11: 1087-1095. 10.1016/S0969-2126(03)00166-7.

    Article  CAS  PubMed  Google Scholar 

  35. Pereira SL, Reeve JN: Histones and nucleosomes in Archaea and Eukarya: a comparative analysis. Extremophiles. 1998, 2: 141-148. 10.1007/s007920050053.

    Article  CAS  PubMed  Google Scholar 

  36. Gangloff YG, Romier C, Thuault S, Werten S, Davidson I: The histone fold is a key structural motif of transcription factor TFIID. Trends Biochem Sci. 2001, 26: 250-257. 10.1016/S0968-0004(00)01741-2.

    Article  CAS  PubMed  Google Scholar 

  37. Wong JT, New DC, Wong JC, Hung VK: Histone-like proteins of the dinoflagellate Crypthecodinium cohnii have homologies to bacterial DNA-binding proteins. Eukaryot Cell. 2003, 2: 646-650. 10.1128/EC.2.3.646-650.2003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Decanniere K, Babu AM, Sandman K, Reeve JN, Heinemann U: Crystal structures of recombinant histones HMfA and HMfB from the hyperthermophilic archaeon Methanothermus fervidus. J Mol Biol. 2000, 303: 35-47. 10.1006/jmbi.2000.4104.

    Article  CAS  PubMed  Google Scholar 

  39. Sandman K, Reeve JN: Archaeal histones and the origin of the histone fold. Curr Opin Microbiol. 2006, 9: 520-525. 10.1016/j.mib.2006.08.003.

    Article  CAS  PubMed  Google Scholar 

  40. Tachiwana H, Kagawa W, Osakabe A, Kawaguchi K, Shiga T, Hayashi-Takanaka Y, Kimura H, Kurumizaka H: Structural basis of instability of the nucleosome containing a testis-specific histone variant human H3T. Proc Natl Acad Sci USA. 2010, 107: 10454-10459. 10.1073/pnas.1003064107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Werten S, Mitschler A, Romier C, Gangloff YG, Thuault S, Davidson I, Moras D: Crystal structure of a subcomplex of human transcription factor TFIID formed by TATA binding protein-associated factors hTAF4 (hTAF(II)135) and hTAF12 (hTAF(II)20). J Biol Chem. 2002, 277: 45502-45509. 10.1074/jbc.M206587200.

    Article  CAS  PubMed  Google Scholar 

  42. Ramakrishnan V: The histone fold: evolutionary questions. Proc Natl Acad Sci USA. 1995, 92: 11328-11330. 10.1073/pnas.92.25.11328.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Alva V, Ammelburg M, Soding J, Lupas AN: On the origin of the histone fold. BMC Struct Biol. 2007, 7: 17-10.1186/1472-6807-7-17.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Grove A: Functional evolution of bacterial histone-like HU proteins. Curr Issues Mol Biol. 2010, 13: 1-12.

    PubMed  Google Scholar 

  45. Oberto J, Drlica K, Rouviere-Yaniv J: Histones, HMG, HU, IHF: Meme combat. Biochimie. 1994, 76: 901-908. 10.1016/0300-9084(94)90014-0.

    Article  CAS  PubMed  Google Scholar 

  46. Ramstein J, Hervouet N, Coste F, Zelwer C, Oberto J, Castaing B: Evidence of a thermal unfolding dimeric intermediate for the Escherichia coli histone-like HU proteins: thermodynamics and structure. J Mol Biol. 2003, 331: 101-121. 10.1016/S0022-2836(03)00725-3.

    Article  CAS  PubMed  Google Scholar 

  47. Greco C, Fantucci P, De Gioia L: In silico functional characterization of a double histone fold domain from the Heliothis zea virus 1. BMC Bioinformatics. 2005, 6 (Suppl 4): S15-10.1186/1471-2105-6-S4-S15.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Sondermann H, Soisson SM, Bar-Sagi D, Kuriyan J: Tandem histone folds in the structure of the N-terminal segment of the ras activator Son of Sevenless. Structure. 2003, 11: 1583-1593. 10.1016/j.str.2003.10.015.

    Article  CAS  PubMed  Google Scholar 

  49. Zhou Z, Feng H, Hansen DF, Kato H, Luk E, Freedberg DI, Kay LE, Wu C, Bai Y: NMR structure of chaperone Chz1 complexed with histones H2A.Z-H2B. Nat Struct Mol Biol. 2008, 15: 868-869. 10.1038/nsmb.1465.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Greco C, Sacco E, Vanoni M, De Gioia L: Identification and in silico analysis of a new group of double-histone fold-containing proteins. J Mol Model. 2005, 12: 76-84. 10.1007/s00894-005-0008-8.

    Article  CAS  PubMed  Google Scholar 

  51. Birck C, Poch O, Romier C, Ruff M, Mengus G, Lavigne AC, Davidson I, Moras D: Human TAF(II)28 and TAF(II)18 interact through a histone fold encoded by atypical evolutionary conserved motifs also found in the SPT3 family. Cell. 1998, 94: 239-249. 10.1016/S0092-8674(00)81423-3.

    Article  CAS  PubMed  Google Scholar 

  52. Hu H, Liu Y, Wang M, Fang J, Huang H, Yang N, Li Y, Wang J, Yao X, Shi Y, Li G, Xu RM: Structure of a CENP-A-histone H4 heterodimer in complex with chaperone HJURP. Genes Dev. 2011, 25: 901-906. 10.1101/gad.2045111.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Aravind L, Anantharaman V, Balaji S, Babu MM, Iyer LM: The many faces of the helix-turn-helix domain: transcription regulation and beyond. FEMS Microbiol Rev. 2005, 29: 231-262.

    Article  CAS  PubMed  Google Scholar 

  54. Pabo CO, Sauer RT: Protein-DNA recognition. Annu Rev Biochem. 1984, 53: 293-321. 10.1146/annurev.bi.53.070184.001453.

    Article  CAS  PubMed  Google Scholar 

  55. Zhang AP, Pigli YZ, Rice PA: Structure of the LexA-DNA complex and implications for SOS box measurement. Nature. 2010, 466: 883-886. 10.1038/nature09200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Meinhart A, Blobel J, Cramer P: An extended winged helix domain in general transcription factor E/IIE alpha. J Biol Chem. 2003, 278: 48267-48274. 10.1074/jbc.M307874200.

    Article  CAS  PubMed  Google Scholar 

  57. Parkinson G, Gunasekera A, Vojtechovsky J, Zhang X, Kunkel TA, Berman H, Ebright RH: Aromatic hydrogen bond in sequence-specific protein DNA recognition. Nat Struct Biol. 1996, 3: 837-841. 10.1038/nsb1096-837.

    Article  CAS  PubMed  Google Scholar 

  58. Rupert PB, Mollah AK, Mossing MC, Matthews BW: The structural basis for enhanced stability and reduced DNA binding seen in engineered second-generation Cro monomers and dimers. J Mol Biol. 2000, 296: 1079-1090. 10.1006/jmbi.1999.3498.

    Article  CAS  PubMed  Google Scholar 

  59. Stella S, Cascio D, Johnson RC: The shape of the DNA minor groove directs binding by the DNA-bending protein Fis. Genes Dev. 2010, 24: 814-826. 10.1101/gad.1900610.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Eicken C, Pennella MA, Chen X, Koshlap KM, VanZile ML, Sacchettini JC, Giedroc DP: A metal-ligand-mediated intersubunit allosteric switch in related SmtB/ArsR zinc sensor proteins. J Mol Biol. 2003, 333: 683-695. 10.1016/j.jmb.2003.09.007.

    Article  CAS  PubMed  Google Scholar 

  61. Wisedchaisri G, Wu M, Rice AE, Roberts DM, Sherman DR, Hol WG: Structures of Mycobacterium tuberculosis DosR and DosR-DNA complex involved in gene activation during adaptation to hypoxic latency. J Mol Biol. 2005, 354: 630-641. 10.1016/j.jmb.2005.09.048.

    Article  CAS  PubMed  Google Scholar 

  62. Hong M, Fuangthong M, Helmann JD, Brennan RG: Structure of an OhrR-ohrA operator complex reveals the DNA binding mechanism of the MarR family. Mol Cell. 2005, 20: 131-141. 10.1016/j.molcel.2005.09.013.

    Article  CAS  PubMed  Google Scholar 

  63. Liu T, DeRose EF, Mullen GP: Determination of the structure of the DNA binding domain of gamma delta resolvase in solution. Protein Sci. 1994, 3: 1286-1295. 10.1002/pro.5560030815.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Dangi B, Gronenborn AM, Rosner JL, Martin RG: Versatility of the carboxy-terminal domain of the alpha subunit of RNA polymerase in transcriptional activation: use of the DNA contact site as a protein contact site for MarA. Mol Microbiol. 2004, 54: 45-59. 10.1111/j.1365-2958.2004.04250.x.

    Article  CAS  PubMed  Google Scholar 

  65. Krishna SS, Majumdar I, Grishin NV: Structural classification of zinc fingers: survey and summary. Nucleic Acids Res. 2003, 31: 532-550. 10.1093/nar/gkg161.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Klug A: The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annu Rev Biochem. 2010, 79: 213-231. 10.1146/annurev-biochem-010909-095056.

    Article  CAS  PubMed  Google Scholar 

  67. Wolfe SA, Nekludova L, Pabo CO: DNA recognition by Cys2His2 zinc finger proteins. Annu Rev Biophys Biomol Struct. 2000, 29: 183-212. 10.1146/annurev.biophys.29.1.183.

    Article  CAS  PubMed  Google Scholar 

  68. Lee BM, Xu J, Clarkson BK, Martinez-Yamout MA, Dyson HJ, Case DA, Gottesfeld JM, Wright PE: Induced fit and "lock and key" recognition of 5 S RNA by zinc fingers of transcription factor IIIA. J Mol Biol. 2006, 357: 275-291. 10.1016/j.jmb.2005.12.010.

    Article  CAS  PubMed  Google Scholar 

  69. Omichinski JG, Pedone PV, Felsenfeld G, Gronenborn AM, Clore GM: The solution structure of a specific GAGA factor-DNA complex reveals a modular binding mode. Nat Struct Biol. 1997, 4: 122-132. 10.1038/nsb0297-122.

    Article  CAS  PubMed  Google Scholar 

  70. Elango N, Radhakrishnan R, Froland WA, Wallar BJ, Earhart CA, Lipscomb JD, Ohlendorf DH: Crystal structure of the hydroxylase component of methane monooxygenase from Methylosinus trichosporium OB3b. Protein Sci. 1997, 6: 556-568.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Langelier MF, Planck JL, Roy S, Pascal JM: Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity. J Biol Chem. 2011, 286: 10690-10701. 10.1074/jbc.M110.202507.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. McCormick MS, Sazinsky MH, Condon KL, Lippard SJ: X-ray crystal structures of manganese(II)-reconstituted and native toluene/o-xylene monooxygenase hydroxylase reveal rotamer shifts in conserved residues and an enhanced view of the protein interior. J Am Chem Soc. 2006, 128: 15108-15110. 10.1021/ja064837r.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Houbaviy HB, Usheva A, Shenk T, Burley SK: Cocrystal structure of YY1 bound to the adeno-associated virus P5 initiator. Proc Natl Acad Sci USA. 1996, 93: 13577-13582. 10.1073/pnas.93.24.13577.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Tidow H, Andreeva A, Rutherford TJ, Fersht AR: Solution structure of the U11-48 K CHHC zinc-finger domain that specifically binds the 5' splice site of U12-type introns. Structure. 2009, 17: 294-302. 10.1016/j.str.2008.11.013.

    Article  CAS  PubMed  Google Scholar 

  75. Samara NL, Datta AB, Berndsen CE, Zhang X, Yao T, Cohen RE, Wolberger C: Structural insights into the assembly and function of the SAGA deubiquitinating module. Science. 2010, 328: 1025-1029. 10.1126/science.1190049.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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PAT conceived the idea, analyzed the data, and co-wrote the paper. KS, CEH, JC, and BS performed the search and analysis. KS co-wrote the paper. All authors read and approved the final manuscript.

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Sousounis, K., Haney, C.E., Cao, J. et al. Conservation of the three-dimensional structure in non-homologous or unrelated proteins. Hum Genomics 6, 10 (2012). https://doi.org/10.1186/1479-7364-6-10

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