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Homology

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  1. Outline • Homology • Function annotation transfer • Domains • Protein-family Databases • Profile-HMMs • Pfam database • How to build a new (Pfam) protein family EMBO Workshop, Cape Town, 2014

  2. Homology EMBO Workshop, Cape Town, 2014

  3. Definition: Two proteins are homologous if they share a common ancestor, i.e. they are evolutionary related EMBO Workshop, Cape Town, 2014

  4. B A C C B B A B A A homologous homologous homologous homologous homologous Symmetric AND Transitive

  5. Detecting homology EMBO Workshop, Cape Town, 2014

  6. Sequence similarity Human: 1 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDEMKASE 60 MGLSDGEWQLVLNVWGKVEAD GHGQEVLI LFK HPETL KFDKFK LKSE MK SE Mouse: 1 MGLSDGEWQLVLNVWGKVEADLAGHGQEVLIGLFKTHPETLDKFDKFKNLKSEEDMKGSE 60 Human: 61 DLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQVLQSKH 120 DLKKHG TVLTALG ILKKKG H AEI PLAQSHATKHKIPVKYLEFISE II VL H Mouse: 61 DLKKHGCTVLTALGTILKKKGQHAAEIQPLAQSHATKHKIPVKYLEFISEIIIEVLKKRH 120 Human: 121 PGDFGADAQGAMNKALELFRKDMASNYKELGFQG 154 GDFGADAQGAM KALELFR D A YKELGFQG Mouse: 121 SGDFGADAQGAMSKALELFRNDIAAKYKELGFQG 154 By excess similarity (see Pearson CurrProtocBioinformatics 2013) Statistical significance (e.g. E-values) EMBO Workshop, Cape Town, 2014

  7. Structural similarity 2G2X: 1 MAYWLMKSEPDELSIEALARLGEARWDGVRNYQARNFLRAMSVGDEFFFYH-----SSCP 55 MAYWL D W Y N VGD Y 2P5D: 4 MAYWLCITNEDNWKVIKEKKI----WGVAERY--KNTINKVKVGDKLIIYEIQRSGKDYK 57 2G2X: 56 QPGIAGIARITRAAYPD------PTALDPESHY 82 P I G Y D PT P 2P5D: 58 PPYIRGVYEVVSEVYKDSSKIFKPTPRNPNEKF 90 Excess sequence similarity? EMBO Workshop, Cape Town, 2014

  8. Structural similarity 2P5D 2G2X EMBO Workshop, Cape Town, 2014

  9. Structural similarity 2P5D 2G2X EMBO Workshop, Cape Town, 2014

  10. Structural similarity 2P5D 2G2X Z-score = 12.2 RMSD = 2.9 Lali = 122 %id =20 DALI: http://ekhidna.biocenter.helsinki.fi/dali_lite/start

  11. Genome context http://www.microbesonline.org EMBO Workshop, Cape Town, 2014

  12. Genomic context http://www.microbesonline.org EMBO Workshop, Cape Town, 2014

  13. Genomic context http://www.microbesonline.org EMBO Workshop, Cape Town, 2014

  14. Origins of homology in proteins EMBO Workshop, Cape Town, 2014

  15. Origin of homology in proteins • Speciation (orthology) • Gene duplication (paralogy) • Horizontal gene transfer (xenology) • Whole genome duplication (ohnology) • Gametology EMBO Workshop, Cape Town, 2014

  16. Orthology Myoglobin: Serves as a reserve supply of oxygen and facilitates the movement of oxygen within muscles. EMBO Workshop, Cape Town, 2014

  17. Origin of protein homology • Speciation (orthology) • Gene duplication (paralogy) • Horizontal gene transfer (xenology) • Whole genome duplication (ohnology) • Gametology EMBO Workshop, Cape Town, 2014

  18. Paralogy Myoglobin: Serves as a reserve supply of oxygen and facilitates the movement of oxygen within muscles. Hemoglobin: Oxygen-transport protein in red-blood cells of vertebrates EMBO Workshop, Cape Town, 2014

  19. EMBO Workshop, Cape Town, 2014

  20. C B Myo Hemo Myo Ancestral Globin A EMBO Workshop, Cape Town, 2014

  21. C B Myo Hemo Myo Ancestral Globin A EMBO Workshop, Cape Town, 2014

  22. C B Hemo Hemo Myo Myo Hemo Myo Ancestral Globin A EMBO Workshop, Cape Town, 2014

  23. Origin of protein homology • Speciation (orthology) • Gene duplication (paralogy) • Horizontal gene transfer (xenology) • Whole genome duplication (ohnology) • Gametology, Synology EMBO Workshop, Cape Town, 2014

  24. Mindell and Meyer Trends in Ecology and Evolution 2001

  25. Homology: why bother? Slide courtesy of Alex Mitchell (EMBL-EBI) EMBO Workshop, Cape Town, 2014

  26. Homology: why bother? Structure (homology modeling) Homology Function? EMBO Workshop, Cape Town, 2014

  27. Protein function(s) Schubert et al. Nat. Struct. Biol. 5 (1998) EMBO Workshop, Cape Town, 2014

  28. The Gene Ontology (GO) • A way to capture biological knowledge in a written and computable form • A set of concepts • and their relationships • to each other www.ebi.ac.uk/QuickGO Slide courtesy of Alex Mitchell (EMBL-EBI) EMBO Workshop, Cape Town, 2014

  29. GO: 3 ontologies in 1 • protein kinase activity • insulin receptor activity An elemental activity or task or job 1. Molecular Function 2. Biological Process A commonly recognised series of events • cell division • mitochondrion • mitochondrial matrix • mitochondrial inner membrane 3. Cellular Component Where a gene product is located Slide courtesy of Alex Mitchell (EMBL-EBI) EMBO Workshop, Cape Town, 2014

  30. Protein Families EMBO Workshop, Cape Town, 2014

  31. Globins in Human http://www.studyblue.com/notes/note/n/exam-3/deck/8955883

  32. Definition: We call ‘family’ a group of evolutionary related proteins or protein regions EMBO Workshop, Cape Town, 2014

  33. Why protein families? A P EMBO Workshop, Cape Town, 2014

  34. Why protein families? Human: 1 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDEMKASE 60 MGLSDGEWQLVLNVWGKVEAD GHGQEVLI LFK HPETL KFDKFK LKSE MK SE Mouse: 1 MGLSDGEWQLVLNVWGKVEADLAGHGQEVLIGLFKTHPETLDKFDKFKNLKSEEDMKGSE 60 Human: 61 DLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQVLQSKH 120 DLKKHG TVLTALG ILKKKG H AEI PLAQSHATKHKIPVKYLEFISE II VL H Mouse: 61 DLKKHGCTVLTALGTILKKKGQHAAEIQPLAQSHATKHKIPVKYLEFISEIIIEVLKKRH 120 Human: 121 PGDFGADAQGAMNKALELFRKDMASNYKELGFQG 154 GDFGADAQGAM KALELFR D A YKELGFQG Mouse: 121 SGDFGADAQGAMSKALELFRNDIAAKYKELGFQG 154 EMBO Workshop, Cape Town, 2014

  35. Why protein families? Human: 1 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDEMKASE 60 MGLSDGEWQLVLNVWGKVEAD GHGQEVLI LFK HPETL KFDKFK LKSE MK SE Mouse: 1 MGLSDGEWQLVLNVWGKVEADLAGHGQEVLIGLFKTHPETLDKFDKFKNLKSEEDMKGSE 60 Human: 61 DLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQVLQSKH 120 DLKKHG TVLTALG ILKKKG H AEI PLAQSHATKHKIPVKYLEFISE II VL H Mouse: 61 DLKKHGCTVLTALGTILKKKGQHAAEIQPLAQSHATKHKIPVKYLEFISEIIIEVLKKRH 120 Human: 121 PGDFGADAQGAMNKALELFRKDMASNYKELGFQG 154 GDFGADAQGAM KALELFR D A YKELGFQG Mouse: 121 SGDFGADAQGAMSKALELFRNDIAAKYKELGFQG 154 EMBO Workshop, Cape Town, 2014

  36. B C A D P E H F G EMBO Workshop, Cape Town, 2014

  37. We can detect functionally important residues EMBO Workshop, Cape Town, 2014

  38. We can detect functionally important residues EMBO Workshop, Cape Town, 2014

  39. We have a window open on evolutionary diversity Human: 1 MGLSDGEWQLVLNVWGKVEADIPGHGQEVLIRLFKGHPETLEKFDKFKHLKSEDEMKASE 60 MGLSDGEWQLVLNVWGKVEAD GHGQEVLI LFK HPETL KFDKFK LKSE MK SE Mouse: 1 MGLSDGEWQLVLNVWGKVEADLAGHGQEVLIGLFKTHPETLDKFDKFKNLKSEEDMKGSE 60 Human: 61 DLKKHGATVLTALGGILKKKGHHEAEIKPLAQSHATKHKIPVKYLEFISECIIQVLQSKH 120 DLKKHG TVLTALG ILKKKG H AEI PLAQSHATKHKIPVKYLEFISE II VL H Mouse: 61 DLKKHGCTVLTALGTILKKKGQHAAEIQPLAQSHATKHKIPVKYLEFISEIIIEVLKKRH 120 Human: 121 PGDFGADAQGAMNKALELFRKDMASNYKELGFQG 154 GDFGADAQGAM KALELFR D A YKELGFQG Mouse: 121 SGDFGADAQGAMSKALELFRNDIAAKYKELGFQG 154 EMBO Workshop, Cape Town, 2014

  40. We have a window open on evolutionary diversity

  41. Example (using homology for protein annotation) EMBO Workshop, Cape Town, 2014

  42. H. influenzae protein (3M71) 1.20 Å Chen et al. Nature 467 (2010) TUM, January 2013 EMBO Workshop, Cape Town, 2014 New York Consortium on Membrane Protein Structure (NYCOMPS)

  43. TUM, January 2013

  44. Thomine and Barbier-BrygooNature 467:1058-59 (2010) EMBO Workshop, Cape Town, 2014

  45. Thomine and Barbier-BrygooNature 467:1058-59 (2010) EMBO Workshop, Cape Town, 2014

  46. Chen et al. Nature 467 (2010) EMBO Workshop, Cape Town, 2014

  47. Chen et al. Nature 467 (2010) EMBO Workshop, Cape Town, 2014