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Structure and evolution of IDPs

Structure and evolution of IDPs. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. Why do we want to characterize/predict IDPs?. 1) Find new ones (460 in DisProt vs. tens of thousands). 2) Describe our protein.

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Structure and evolution of IDPs

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  1. Structure and evolution of IDPs Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary

  2. Why do we want to characterize/predict IDPs? 1) Find new ones (460 in DisProt vs. tens of thousands) 2) Describe our protein

  3. Why do we want to describe the structure of IDPs in detail? Extend the structure-function paradigm

  4. To characterize… In the free state Structure In the bound state

  5. Structural levels Sequence (primary) Local (secondary) Structure Global (tertiary)

  6. 1) Primary structure

  7. Primary structure (sequence) of IDPs Dunker et al. (2001) J. Mol. Graph. Model. 19, 26

  8. Low-complexity regions in proteins Wootton (1994) Comp. Chem. 18, 269

  9. Low complexity:Drosophila mastermind

  10. Drosophila mastermind MDAGGLPVFQSASQAAAAAVAQQQQQQQQQQQQQQQQQQQHLNLQLHQQHLQQQQSLGIHLQQQQQLQLQQQQQHNAQAQQQ QQLQVQQQQQQRQQQQQQQQQHSLYNANLAAAGGIVGGLVPGGNGAGGVALQQVFGGPNGNNNSNNNNNSNNNSININNGNI SPGDGLPTKRQPILDRLRRRMENYRRRQTDCVPRYEQTFSTVCEQQNHETSALQKRFLESKNKRAAKKTEKKLPETQQQAQT QMLAGQLQSSVHVQQKILKRPADDVDNGAENYEPPQKLPNNNNNNNNNNNNNNNSSSGVGGGSENLTKFSVEIVQQLEFTTS AANSQPQQISTNVTVKALTNTSVKSEPGVGGGRGRHQQQQQHQQHQQQQHQQQQHQQHQQHQQQQQHQQQQHQQQQHQQQQQ QHHHQQQQQQGGGLGGLGNNGRGGGGPGGGGHMATGPGGVGVGMGPNMMSAQQKSALGNLANLVECKREPDHDFPDLGSLAK DGANGQFPGFPDLLGDDNSENNDTFKDLINNLHDFNPSFLDGFDEKPLLDIKTEDGIKVEPPNAQDLINSLNVKSETGLGHG FGGFGVGLGLDPQSMKMRPGVGFQNGPNGNANAGNGGPTAGGGGGGNGPGGLMSEHSLAAQTLKQMAEQHQHKSAMGGMGGF HVPPHGMQQQQPQQQQQAPQQQQQQHGQMMGGPGQGQQQQQQQQPRYNDYGGGFPNDFAMGPNPTQQQQQHLPPQFHQKAPG GGPGMNVQQNFLDIKQELFYSSPNDFDLKHLQQQQAMQQQQQQQQQQQQQQQHHAQQQQQHPNGPNMGVPMGGAGNFAKQQQ QQVPTPQQQQQQQLQQQQQQYSPFSNQNANANFLNCPPRGGPQGNQAPGNMPQQQQQQPQQQQQPPRGPQSNPNAVPGGNAA NATQQQQQQQQQQQQQQQQQQQQQQQATTTTLQMKQTQQLHISQQGGGSHGIQVSAGQHLHLSSDMKSNVSVAAQQGVFFSQ QQAAQQQQQQQQQPGNAGPNPQQQQQQPHGGNAGANGGGPNGPQQQQPNQNMNNSNVPSDGFSLSQSQSMNFTQQQQQQAAA AAAAAAAAQQQQAAAAQQQQQQVPPNMRQRQTQAQAAAAAAAAAAAQAQAAANANGGPGGNVPLMQQQQQTPGGVPVGAGSG NASVGVPVSAGGPNNGAMNQLGGPMGGMPGMQMGGPGGVPINPMQMNPNGGAPNAQMMMGGNGGGPVPAASQAKFLQQQQIM RAQAMQHQQQVQQHMAGARPPPPEYNATKAQLMQAQMMQQTVGGGGGGGVGVGVGVGGGVGGGGGAGRFPNSAAQAAAMRRM TQQPIPPSGPMMRPQHAAMYMQQHGGAGGGPRGGMGGPYGGGGVGGAGGPMGGGGGGQQQQQRPPNVQVTPDGMPMGSQQEW RHMMMTQQQQQMGFGPGGPMRQGPGGFNGGNFMPNGAPNAPGNGPNGGGGGGMMPGPNGPQMQLTPAQMQQQHMRQQQQQQH MGPGGGGGGGGGNMQMQQLLQQQQNAAAGGGGGMMATQMQMTSIHMSQTQQQQQLTMQQQQFVQSTSTTTTHQQQQQLQLQM QSQSGGPGGNGPSNNNGANQAGGVGVGVGVGVGVGVVGSSATIASASSISQTINSVVANSNDLCLEFLDNLPDGNFSTQDLI NSLDNDNFNIQDILQ

  11. 2) Secondary structure Structure in the free state (3 examples)

  12. CREB-KID - CBP-KIX binding and NMR Radhakrishnan et al. (1998) FEBS Lett. 430, 317

  13. FlgM: evidence for disorder in vivo Plaxco and Gross (1997) Nature, 386, 657

  14. FlgM - sigma 28 binding and NMR Sorenson (2004) Mol. Cell 14, 127

  15. p27 – CycA/Cdk2 binding (NMR, MD) Sivakolundu et al. (2005) JMB 353, 1118

  16. And a fourth: polyproline II helix SH3-PPII Wikipedia

  17. PPII PPII helix conformation is common in IDPs Dominates in : a-casein a-synuclein tau wheat gluten Raman optical activity (ROA) Syme et al. (2002) EJB 269, 148

  18. 2) Secondary structure Structure in the bound state

  19. p27Kip1 Tcf3 IA3 Cdk2 Asp prot. FnBP fibronectin CycA b-catenin Complexes of IDPs in PDB

  20. 31.3 % 21.9 % 44.8 % 10.9 % Secondary structural elements Helix globular IDP

  21. Comparison of free and bound states: what does it tell us ?

  22. Local secondary structural elements in IDPs: molecular recognition 1) disorder pattern molecular recognition element MoRE, MoRF 2) consensus sequence: linear motif LM, ELM, SLiM 3) local predictable structure preformed structural element PSE

  23. 1) Disorder pattern: MoRE in tumor suppressor p53 Uversky et al. (2005) J. Mol. Recogn. 18, 343

  24. 2) Consensus sequences: ELMs

  25. ELMs and local disorder Fuxreiter et al (2006) Bioinformatics, 23, 950

  26. 3) Predictability of structure: preformed structural elements, PSEs p27Kip1 Tcf3 IA3 Cdk2 Asp prot. FnBP fibronectin CycA b-catenin

  27. PSE: predictability of secondary structure IDP Partner Fuxreiter et al. (2004) JMB 338, 1015

  28. MoRE PSE MorE, LM, PSE: devices of effective recognition

  29. Sequential mechanism of p27 binding 45 Lacy et al (2004) NSMB 11, 358

  30. 3) Tertiary structure

  31. Structural ensemble of a-synuclein (NMR paramagnetic relaxation enhancement) Dedmon et al. (2005) JACS 127, 476

  32. SAXS distance-distribution function and topology of cellulase E Von Ossowski et al. (2005) Biophys. J. 88, 2823

  33. Global (tertiary) structure of IUPs IUPRC U (RC) IUPPMG PMG MG Native Uversky (2002) Prot. Sci. 11, 739

  34. p27 A lesson from denatured states of globular proteins: spatial topology in denatured state resembles native structure (David Shortle) Gillespie et al (1997) JMB 268, 170

  35. Models Protein trinity Protein quartet ordered ordered PMG molten globule random coil MG RC (Dunker) (Uversky)

  36. The evolution of protein disorder Generation Evolution

  37. Disorder in complete genomes (PONDR) Dunker et al. (2000) Genome Inf. 11, 161

  38. Disorder in complete genomes (DISOPRED) Ward et al. (2004) JMB 337, 635

  39. IDPs: high frequency in proteomes yeast coli Tompa et al. (2006) J. Prot. Res5, 1996

  40. Structural disorder: evolutionary success story LDR (40<) protein, % 60 E 40 A 20 B 0 Domain of life Vucetic et al. (2002) Proteins 52, 573

  41. The evolution of protein disorder de novogeneration Generation gene duplication lateral gene transfer, LGT Evolution

  42. The evolution of protein disorder de novogeneration Generation gene duplication lateral gene transfer, LGT Evolution Pointmutation Mutations

  43. Rapid evolution by point mutations Brown et al. (2002) J. Mol. Evol. 55, 104

  44. Non-synonymous vs. synonymous substitutions Synonymous (Ks) Point mutations Non-synonymous (Ka) Nonsense 0.1-0.2: „functional” Evolution (Ka/Ks): 1.0: „neutral” 1.0: „adaptive”

  45. Rapid evolution of SRY gene SRY: sex determining region on the Y chromosome (testis determining factor)

  46. The evolution of protein disorder de novogeneration Generation gene duplication lateral gene transfer, LGT Evolution Pointmutation Mutations Repeat expansion

  47. RNA polymerase II

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