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Functional classification of IDPs

Functional classification of IDPs. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. 1. Fun ctional advantages 2. Fun ctional classification (7 basic mechanisms) 3. Func t ion al classification (28 partners-effects)

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Functional classification of IDPs

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  1. Functional classification of IDPs Peter Tompa Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary

  2. 1. Functional advantages 2. Functional classification (7 basic mechanisms) 3. Functional classification (28 partners-effects) 4. The relationship of schemes: extension of the GO system?

  3. 1) Functional advantages of disorder

  4. i) Entropic-chain functions

  5. ii) Specificity without strong binding (reversibility, inducibility)

  6. iii) Large binding surfaces in complexes (specificity, multiple partners) IDP Globular Gunasekaran (2004) JMB 341, 1327

  7. iv) Fast binding - first observed in DNA renaturation - hnRNAP A1 no protein Pontius (1990) PNAS 87, 8403

  8. ”Fly-casting” model Shoemaker B. A, (2000) PNAS 8868-8873 Speeding molecular recognition by using the folding funnel: the fly-casting mechanism

  9. ”Protein fishing” model clathrin AP180

  10. v) Binding promiscuity (one-to-many signaling, moonlighting)

  11. IUPs with multiple talents: moonlighting

  12. vi) Flexibility in the assembly of complexes

  13. Disorder correlates with complex size single 11-100 2-4 5-10 Hegyi et al. (2007) BMC Struct. Biol. 7, 65

  14. 2) Functional classification: 7 basic mechanisms

  15. Six basic mechanisms of IDPs Tompa (2005) FEBS Lett. 579, 3346

  16. IDP I: entropic chains

  17. Microtubule-associated protein 2 cytoskeleton Tubulin dimers MTs

  18. MAP projection domain: entropic bristle Mukhopadhyay (2001) FEBS Lett. 505, 374

  19. Spacing of MTs in dendrites and axons

  20. V-dependent K+-channel: entropic clock

  21. Titin: an entropic spring (like a piece of rubber)

  22. PEVPPVRVPEVPKEVVPEKKVPAAPPKKPEVTPVKVPEAPKEVVPEKK

  23. Titin PEVK domain: entropic spring

  24. IDPs II: effectors

  25. FlgM: inhibitor of sigma28 transcription factor Plaxco and Gross (1997) Nature, 386, 657

  26. p27: another effector, inhibitor of Cdk2

  27. IDPs III: scavengers

  28. Casein: rapid and high-capacity binding of Ca3(PO4)2 Ca3(PO4)2 Ca2+ + PO43-

  29. MLLILLSVALLALSSAQNLNEDVSQEESPSLIAGNPQGPSP QGGNKPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPP QGDKSRSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPP QGGNKPQGPPPPGKPQGPPPQGDKSQSPRSPPGKPQGPPPQ GGNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPPQ GDKSQSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPQQ GGNRPQGPPPPGKPQGPPPQGDKSRSPQSPPGKPQGPPPQG GNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPAQG GSKSQSARAPPGKPQGPPQQEGNNPQGPPPPAGGNPQQPQA PPAGQPQGPPRPPQGGRPSRPPQ Baxter (1997) Biochemistry 36, 5566 Salivary PRPs: high-capacity binding of tannins

  30. IDPs IV: assemblers 45

  31. p27Kip1 Tcf3 IA3 Cdk2 Asp prot. FnBP fibronectin CycA b-catenin Fibronectin binding protein

  32. High-affinity binding to fibronectin, tethering bacteria to host Schwarz-Linek (2004) JBC 279, 39017

  33. IDPs V: display sites

  34. Ser133 CREB KID phosphorylation induces binding to CBP KIX domain PKA CREB KID Radhakrishnan (1997) Cell 91, 741

  35. cAMP-response element binding protein (CREB) activation

  36. The ELM server http://elm.eu.org/

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

  38. IDPs VI:chaperones

  39. Prediction: very high level of disorder in chaperones regulatory signaling RNA chaperones protein chaperones

  40. Disorder is involved in chaperone function

  41. binding S transfer The entropy-transfer model of disordered chaperones misfolded folded IUP Tompa and Csermely (2004) Faseb J., 18, 1170-1175

  42. IDPs VII:prions

  43. Amyloid: mad-cow disease Patholopgical prion: structure of PrPC GPI * * * (PHGGGWGQ)5 * * * * P102L * * P107L * A127GAAA*AGAVVGGLGG133

  44. Physiological prion: Sup35p, eukaryotic translation release factor3 MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD HVSIIFMGHVDA........

  45. Prion form of Sup35: translation read-through

  46. Prion form of Sup35: translation read-through

  47. 3) Functional classification: 28 partners-effects

  48. Functional classification of IDPs,Dunker 2002 protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel polymerization substrate/ligand binding cofactor/heme binding metal binding acetylation fatty acylation (myristoyl/palmitoyl) glycosylation methylation phosphorylation ADP-ribosylation DNA unwinding DNA bending reg. of proteolysis in vivo autoregulatory not essential/unknown

  49. Functional classification of IDPs,Dunker 2002 protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel polymerization substrate/ligand binding cofactor/heme binding metal binding acetylation fatty acylation (myristoyl/palmitoyl) glycosylation methylation phosphorylation ADP-ribosylation DNA unwinding DNA bending reg. of proteolysis in vivo autoregulatory not essential/unknown assembler effector chaperone

  50. Functional classification of IDPs,Dunker 2002 protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel polymerization substrate/ligand binding cofactor/heme binding metal binding acetylation fatty acylation (myristoyl/palmitoyl) glycosylation methylation phosphorylation ADP-ribosylation DNA unwinding DNA bending reg. of proteolysis in vivo autoregulatory not essential/unknown assembler effector chaperone entropic chain

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