Protodomains: Symmetry-Related Supersecondary Structures in Proteins and Self-Complementarity

  • Philippe YoukharibacheEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1958)


We will consider in this chapter supersecondary structures (SSS) as a set of secondary structure elements (SSEs) found in protein domains. Some SSS arrangements/topologies have been consistently observed within known tertiary structural domains. We use them in the context of repeating supersecondary structures that self-assemble in a symmetric arrangement to form a domain. We call them protodomains (or protofolds). Protodomains are some of the most interesting and insightful SSSs. Within a given 3D protein domain/fold, recognizing such sets may give insights into a possible evolutionary process of duplication, fusion, and coevolution of these protodomains, pointing to possible original protogenes. On protein folding itself, pseudosymmetric domains may point to a “directed” assembly of pseudosymmetric protodomains, directed by the only fact that they are tethered together in a protein chain. On function, tertiary functional sites often occur at protodomain interfaces, as they often occur at domain-domain interfaces in quaternary arrangements.

First, we will briefly review some lessons learned from a previously published census of pseudosymmetry in protein domains (Myers-Turnbull, D. et al., J Mol Biol. 426:2255–2268, 2014) to introduce protodomains/protofolds. We will observe that the most abundant and diversified folds, or superfolds, in the currently known protein structure universe are indeed pseudosymmetric. Then, we will learn by example and select a few domain representatives of important pseudosymmetric folds and chief among them the immunoglobulin (Ig) fold and go over a pseudosymmetry supersecondary structure (protodomain) analysis in tertiary and quaternary structures. We will point to currently available software tools to help in identifying pseudosymmetry, delineating protodomains, and see how the study of pseudosymmetry and the underlying supersecondary structures can enrich a structural analysis. This should potentially help in protein engineering, especially in the development of biologics and immunoengineering.

Key words

Protein structure Protodomains Supersecondary structure Symmetry Pseudosymmetry Immunoengineering Domains Fold Folding Engineering Quaternary structure Immunoglobulins Sm Hfq GPCR Sweet protein FN3 Type I cytokine receptor CHR IL-2R IL-21R GHR GHbp 



I would like to thank Jiyao Wang at NCBI who developed most of iCn3D software and has been working very hard to release the new version of the software to allow some key visualization on time for this paper and all members of the NCBI Structure group headed by Steve Bryant who participated; Peter Rose at SDSC who guided me through RCSB’s symmetry categorizations in quaternary structure and who developed the symmetry visualization in Jmol, used at RCSB and within CE-symm; and Spencer Bliven and Aleix Latifa who developed CE-symm further to allow multilevel symmetry determination, both at the quaternary and tertiary levels simultaneously. A special thought for Guido Capitani who supported that last effort and who passed away last year, far too young, before we had time to join forces on tertiary/quaternary structural analysis. I miss him both at a personal level and scientifically. Thank you to Stella Veretnik for discussions over the years on small beta barrels. Thank you to Phil Bourne who gave me the opportunity to resume work on pseudosymmetry at the NIH while initiated long ago at Columbia University with Cy Levinthal, Barry Honig, and Wayne Hendrickson. Thank you to Tom Misteli at the National Cancer Institute for his support, giving me the opportunity to pursue applications of these concepts in the aim of developing rational design methods for immunotherapy. Finally, I would like to thank Mitchell Ho at the NCI for introducing me to Shark Immunoglobulins.

This research was supported in part by the Intramural Research Program of the National Cancer Institute and the National Library of Medicine, NIH.

Supplementary material

454913_2_En_10_MOESM1_ESM.pdf (2.4 mb)
Figs. S1-S6 Protodomains: Symmetry related SuperSecondary Protein Structures and self-complementarity - Supplement Figures S1-S6 (PDF 2452 kb)


  1. 1.
    Myers-Turnbull D et al (2014) Systematic detection of internal symmetry in proteins using CE-Symm. J Mol Biol 426:2255–2268CrossRefGoogle Scholar
  2. 2.
    Alewine C, Hassan R, Pastan I (2015) Advances in anticancer immunotoxin therapy. Oncologist 20:176–185CrossRefGoogle Scholar
  3. 3.
    Kochenderfer JN, Rosenberg SA (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10:267–276CrossRefGoogle Scholar
  4. 4.
    Chothia C, Lesk AM (1987) Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol 196:901–917CrossRefGoogle Scholar
  5. 5.
    Chothia C, Novotný J, Bruccoleri R, Karplus M (1985) Domain association in immunoglobulin molecules. The packing of variable domains. J Mol Biol 186:651–663CrossRefGoogle Scholar
  6. 6.
    Díaz-Ramos MC, Engel P, Bastos R (2011) Towards a comprehensive human cell-surface immunome database. Immunol Lett 134:183–187CrossRefGoogle Scholar
  7. 7.
    Naeim F, Nagesh Rao P, Song SX, Grody WW (2013) Atlas of hematopathology. Academic, New York, pp 25–46. Scholar
  8. 8.
    McLachlan AD (1972) Gene duplication in carp muscle calcium binding protein. Nat New Biol 240:83–85CrossRefGoogle Scholar
  9. 9.
    Blundell TL, Sewell BT, McLachlan AD (1979) Four-fold structural repeat in the acid proteases. Biochim Biophys Acta 580:24–31CrossRefGoogle Scholar
  10. 10.
    McLachlan AD (1987) Gene duplication and the origin of repetitive protein structures. Cold Spring Harb Symp Quant Biol 52:411–420CrossRefGoogle Scholar
  11. 11.
    Hendrickson WA, Ward KB (1977) Pseudosymmetry in the structure of myohemerythrin. J Biol Chem 252:3012–3018PubMedGoogle Scholar
  12. 12.
    Eck RV, Dayhoff MO (1966) Evolution of the structure of ferredoxin based on living relics of primitive amino acid sequences. Science 152:363–366CrossRefGoogle Scholar
  13. 13.
    Urbain J (1969) Evolution of immunoglobulins and ferredoxins and the occurrence of pseudosymmetrical sequences. Biochem Genet 3:249–269CrossRefGoogle Scholar
  14. 14.
    Barker WC, Ketcham LK, Dayhoff MO (1978) A comprehensive examination of protein sequences for evidence of internal gene duplication. J Mol Evol 10:265–281CrossRefGoogle Scholar
  15. 15.
    Delhaise P, Wuilmart C, Urbain J (1980) Relationships between alpha and beta secondary structures and amino-acid pseudosymmetrical arrangements. Eur J Biochem 105:553–564CrossRefGoogle Scholar
  16. 16.
    Lo Conte L et al (2000) SCOP: a structural classification of proteins database. Nucleic Acids Res 28:257–259CrossRefGoogle Scholar
  17. 17.
    Chandonia J-M, Fox NK, Brenner SE (2017) SCOPe: manual curation and artifact removal in the structural classification of proteins—extended database. J Mol Biol 429:348–355CrossRefGoogle Scholar
  18. 18.
    Sillitoe I, Dawson N, Thornton J, Orengo C (2015) The history of the CATH structural classification of protein domains. Biochimie 119:209–217CrossRefGoogle Scholar
  19. 19.
    Cheng H et al (2014) ECOD: an evolutionary classification of protein domains. PLoS Comput Biol 10:e1003926CrossRefGoogle Scholar
  20. 20.
    Goodsell DS, Olson AJ (2000) Structural symmetry and protein function. Annu Rev Biophys 29:105–153CrossRefGoogle Scholar
  21. 21.
    Levy ED, Pereira-Leal JB, Chothia C, Teichmann SA (2006) 3D complex: a structural classification of protein complexes. PLoS Comput Biol 2:e155CrossRefGoogle Scholar
  22. 22.
    Rose PW et al (2015) The RCSB Protein Data Bank: views of structural biology for basic and applied research and education. Nucleic Acids Res 43:D345–D356CrossRefGoogle Scholar
  23. 23.
    Young JY et al (2018) Worldwide Protein Data Bank biocuration supporting open access to high-quality 3D structural biology data. Database 2018Google Scholar
  24. 24.
    Levy ED, Boeri Erba E, Robinson CV, Teichmann SA (2008) Assembly reflects evolution of protein complexes. Nature 453:1262–1265CrossRefGoogle Scholar
  25. 25.
    Blaber M, Lee J, Longo L (2012) Emergence of symmetric protein architecture from a simple peptide motif: evolutionary models. Cell Mol Life Sci 69:3999–4006CrossRefGoogle Scholar
  26. 26.
    Andrade MA, Perez-Iratxeta C, Ponting CP (2001) Protein repeats: structures, functions, and evolution. J Struct Biol 134:117–131CrossRefGoogle Scholar
  27. 27.
    Abraham A-L, Pothier J, Rocha EPC (2009) Alternative to homo-oligomerisation: the creation of local symmetry in proteins by internal amplification. J Mol Biol 394:522–534CrossRefGoogle Scholar
  28. 28.
    Jones CP, Ferré-D’Amaré AR (2015) RNA quaternary structure and global symmetry. Trends Biochem Sci 40:211–220CrossRefGoogle Scholar
  29. 29.
    Bashan A et al (2003) Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. Mol Cell 11:91–102CrossRefGoogle Scholar
  30. 30.
    Lehn J-M (2002) Toward self-organization and complex matter. Science 295:2400–2403CrossRefGoogle Scholar
  31. 31.
    Lehn J-M (2013) Perspectives in chemistry—steps towards complex matter. Angew Chem Int Ed Engl 52:2836–2850CrossRefGoogle Scholar
  32. 32.
    Gutmanas A et al (2014) PDBe: Protein Data Bank in Europe. Nucleic Acids Res 42:D285–D291CrossRefGoogle Scholar
  33. 33.
    Kinjo AR et al (2017) Protein Data Bank Japan (PDBj): updated user interfaces, resource description framework, analysis tools for large structures. Nucleic Acids Res 45:D282–D288CrossRefGoogle Scholar
  34. 34.
    Marchler-Bauer A et al (2015) CDD: NCBI’s conserved domain database. Nucleic Acids Res 43:D222–D226CrossRefGoogle Scholar
  35. 35.
    Madej T et al (2014) MMDB and VAST+: tracking structural similarities between macromolecular complexes. Nucleic Acids Res 42:D297–D303CrossRefGoogle Scholar
  36. 36.
    Wang Y, Geer LY, Chappey C, Kans JA, Bryant SH (2000) Cn3D: sequence and structure views for Entrez. Trends Biochem Sci 25:300–302CrossRefGoogle Scholar
  37. 37.
    Madej T et al (2012) MMDB: 3D structures and macromolecular interactions. Nucleic Acids Res 40:D461–D464CrossRefGoogle Scholar
  38. 38.
    Kim C, Basner J, Lee B (2010) Detecting internally symmetric protein structures. BMC Bioinformatics 11:303CrossRefGoogle Scholar
  39. 39.
    Tai C-H, Paul R, Dukka KC, Shilling JD, Lee B (2014) SymD webserver: a platform for detecting internally symmetric protein structures. Nucleic Acids Res 42:W296–W300CrossRefGoogle Scholar
  40. 40.
    Wang J, Youkharibache P, Zhang D, Lanczycki CJ, Geer RC, Madej T, Phan L et al (2018) iCn3D, a web-based 3D viewer for the visualization of biomolecular structure and sequence annotation. bioRxiv.
  41. 41.
    Jmol: an open-source browser-based HTML5 viewer and stand-alone Java viewer for chemical structures in 3D.
  42. 42.
    Rose AS, Hildebrand PW (2015) NGL Viewer: a web application for molecular visualization. Nucleic Acids Res 43:W576–W579CrossRefGoogle Scholar
  43. 43.
    Stivala A, Wybrow M, Wirth A, Whisstock JC, Stuckey PJ (2011) Automatic generation of protein structure cartoons with Pro-origami. Bioinformatics 27:3315–3316CrossRefGoogle Scholar
  44. 44.
    Youkharibache P (2017) Twelve elements of visualization and analysis for tertiary and quaternary structure of biological molecules. bioRxiv 153528. 10.1101/153528Google Scholar
  45. 45.
    Mura C, Randolph PS, Patterson J, Cozen AE (2013) Archaeal and eukaryotic homologs of Hfq: A structural and evolutionary perspective on Sm function. RNA Biol 10:636–651CrossRefGoogle Scholar
  46. 46.
    Youkharibache P et al (2019) The small β-barrel domain: a survey-based structural analysis. Structure 27 (1): 6–26. Scholar
  47. 47.
    Serganov A, Huang L, Patel DJ (2009) Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch. Nature 458:233–237CrossRefGoogle Scholar
  48. 48.
    Patikoglou GA et al (1999) TATA element recognition by the TATA box-binding protein has been conserved throughout evolution. Genes Dev 13:3217–3230CrossRefGoogle Scholar
  49. 49.
    Stanfield RL, Dooley H, Flajnik MF, Wilson IA (2004) Crystal structure of a shark single-domain antibody V region in complex with lysozyme. Science 305:1770–1773CrossRefGoogle Scholar
  50. 50.
    Streltsov VA et al (2004) Structural evidence for evolution of shark Ig new antigen receptor variable domain antibodies from a cell-surface receptor. Proc Natl Acad Sci U S A 101:12444–12449CrossRefGoogle Scholar
  51. 51.
    Feige MJ et al (2014) The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins. Proc Natl Acad Sci U S A 111:8155–8160CrossRefGoogle Scholar
  52. 52.
    Kabat EA, Wu TT, Reid-Miller M, Perry HM, Gottesman KS (1987) Sequences of proteins of lmmunologlcal interest, 4th ed. National Institutes of Health, BethesdaGoogle Scholar
  53. 53.
    Lefranc M-P et al (2003) IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev Comp Immunol 27:55–77CrossRefGoogle Scholar
  54. 54.
    Zhang Y-F, Ho M (2017) Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples. MAbs 9:419–429CrossRefGoogle Scholar
  55. 55.
    Siupka P, Hamming OT, Kang L, Gad HH, Hartmann R (2015) A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane. Genes Immun 16:405–413CrossRefGoogle Scholar
  56. 56.
    Hamming OJ et al (2012) Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals that sugar chain interacting with WSXWS motif is integral part of IL-21R. J Biol Chem 287:9454–9460CrossRefGoogle Scholar
  57. 57.
    Baumgartner JW, Wells CA, Chen CM, Waters MJ (1994) The role of the WSXWS equivalent motif in growth hormone receptor function. J Biol Chem 269:29094–29101PubMedGoogle Scholar
  58. 58.
    Forrest L, Structural R (2015) Symmetry in membrane proteins. Annu Rev Biophys 44:311–337CrossRefGoogle Scholar
  59. 59.
    Forrest LR (2013) Structural biology. (Pseudo-)symmetrical transport. Science 339:399–401CrossRefGoogle Scholar
  60. 60.
    Feng L, Frommer WB (2015) Structure and function of SemiSWEET and SWEET sugar transporters. Trends Biochem Sci 40:480–486CrossRefGoogle Scholar
  61. 61.
    Hu Y-B et al (2016) Phylogenetic evidence for a fusion of archaeal and bacterial SemiSWEETs to form eukaryotic SWEETs and identification of SWEET hexose transporters in the amphibian chytrid pathogen Batrachochytrium dendrobatidis. FASEB J 30:3644–3654CrossRefGoogle Scholar
  62. 62.
    Choi S, Jeon J, Yang J-S, Kim S (2008) Common occurrence of internal repeat symmetry in membrane proteins. Proteins 71:68–80CrossRefGoogle Scholar
  63. 63.
    Palczewski K et al (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745CrossRefGoogle Scholar
  64. 64.
    Li J, Edwards PC, Burghammer M, Villa C, Schertler GFX (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol 343:1409–1438CrossRefGoogle Scholar
  65. 65.
    Wu H et al (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344:58–64CrossRefGoogle Scholar
  66. 66.
    Christopher JA et al (2015) Fragment and structure-based drug discovery for a class C GPCR: discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem 58:6653–6664CrossRefGoogle Scholar
  67. 67.
    Youkharibache P, Tran A, Abrol R (2018) 7-Transmembrane Helical (7TMH) Proteins: Pseudo-Symmetry and Conformational Plasticity. bioRxiv. Scholar
  68. 68.
    Stamm M, Forrest LR (2015) Structure alignment of membrane proteins: comparison of available tools and a consensus strategy. Proteins 83(9):1720–1732CrossRefGoogle Scholar
  69. 69.
    Korkmaz S et al (2017) Quaternary structure evaluation tool for protein assemblies. bioRxiv 224196.
  70. 70.
    Kettle SFA (2007) Symmetry and structure: readable group theory for chemists. Wiley.
  71. 71.
    Liu Y, Eisenberg D (2002) 3D domain swapping: as domains continue to swap. Protein Sci 11:1285–1299CrossRefGoogle Scholar
  72. 72.
    Alva V, Söding J, Lupas AN (2015) A vocabulary of ancient peptides at the origin of folded proteins. elife 4:e09410CrossRefGoogle Scholar
  73. 73.
    Petrey D, Fischer M, Honig B (2009) Structural relationships among proteins with different global topologies and their implications for function annotation strategies. Proc Natl Acad Sci U S A 106:17377–17382CrossRefGoogle Scholar
  74. 74.
    Kellman ME (1996) Symmetry in chemistry from the hydrogen atom to proteins. Proc Natl Acad Sci U S A 93:14287–14294CrossRefGoogle Scholar
  75. 75.
    Leahy DJ, Axel R, Hendrickson WA (1992) Crystal structure of a soluble form of the human T cell coreceptor CD8 at 2.6 A resolution. Cell 68:1145–1162CrossRefGoogle Scholar
  76. 76.
    Chang H-C et al (2005) Structural and mutational analyses of a CD8alphabeta heterodimer and comparison with the CD8alphaalpha homodimer. Immunity 23:661–671CrossRefGoogle Scholar
  77. 77.
    Liu Y, Li X, Qi J, Zhang N, Xia C (2016) The structural basis of chicken, swine and bovine CD8αα dimers provides insight into the co-evolution with MHC I in endotherm species. Sci Rep 6:24788CrossRefGoogle Scholar
  78. 78.
    Zak KM et al (2015) Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure 23:2341–2348CrossRefGoogle Scholar
  79. 79.
    Gorman J et al (2016) Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design. Nat Struct Mol Biol 23:81–90CrossRefGoogle Scholar
  80. 80.
    Prabakaran P et al (2008) Structure of an isolated unglycosylated antibody C(H)2 domain. Acta Crystallogr D Biol Crystallogr 64:1062–1067CrossRefGoogle Scholar
  81. 81.
    Oganesyan V et al (2014) Structural insights into neonatal Fc receptor-based recycling mechanisms. J Biol Chem 289:7812–7824CrossRefGoogle Scholar
  82. 82.
    Bravo J, Staunton D, Heath JK, Jones EY (1998) Crystal structure of a cytokine-binding region of gp130. EMBO J 17:1665–1674CrossRefGoogle Scholar
  83. 83.
    de Vos AM, Ultsch M, Kossiakoff AA (1992) Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255:306–312CrossRefGoogle Scholar
  84. 84.
    Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A 103:2788–2793CrossRefGoogle Scholar
  85. 85.
    Tao Y et al (2015) Structure of a eukaryotic SWEET transporter in a homotrimeric complex. Nature 527:259–263CrossRefGoogle Scholar
  86. 86.
    Xu Y et al (2014) Structures of bacterial homologues of SWEET transporters in two distinct conformations. Nature 515:448–452CrossRefGoogle Scholar
  87. 87.
    Vrentas C et al (2015) Hfqs in Bacillus anthracis: role of protein sequence variation in the structure and function of proteins in the Hfq family. Protein Sci 24:1808–1819CrossRefGoogle Scholar
  88. 88.
    Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346–355CrossRefGoogle Scholar
  89. 89.
    Lu X et al (2008) The effect of H3K79 dimethylation and H4K20 trimethylation on nucleosome and chromatin structure. Nat Struct Mol Biol 15:1122–1124CrossRefGoogle Scholar
  90. 90.
    Pettersen EF et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.National Cancer Institute, NIHBethesdaUSA

Personalised recommendations