title: Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53.
abstract: Using highly purified proteins, we have identified intermediate reactions that lead to the assembly of molecular chaperone complexes with wild-type or mutant p53R175H protein. Hsp90 possesses higher affinity for wild-type p53 than for the conformational mutant p53R175H. The presence of Hsp90 in a complex with wild-type p53 inhibits the binding of Hsp40 and Hsc70 to p53, consequently preventing the formation of wild-type p53-multiple chaperone complexes. The conformational mutant p53R175H can form a stable heterocomplex with Hsp90 only in the presence of Hsc70, Hsp40, Hop and ATP. The anti-apoptotic factor Bag-1 can dissociate Hsp90 from a pre- assembled complex wild-type p53 protein, but it cannot dissociate a pre-assembled p53R175H-Hsp40- Hsc70-Hop-Hsp90 heterocomplex. The results presented here provide possible molecular mechanisms that can help to explain the observed in vivo role of molecular chaperones in the stabilization and cellular localization of wild-type and mutant p53 protein.
authors.affiliation: Department of Molecular Biology, International Institute of Molecular and Cell Biology, UNESCO, Warsaw, Poland.
authors.forename: F W
authors.initials: FW
authors.lastname: King
authors.forename: A
authors.initials: A
authors.lastname: Wawrzynow
authors.forename: J
authors.initials: J
authors.lastname: Höhfeld
authors.forename: M
authors.initials: M
authors.lastname: Zylicz
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016227:Benzoquinones; D002352:Carrier Proteins / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases; D047029:Lactams, Macrocyclic; D008954:Models, Biological; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C091732:BCL2-associated athanogene 1 protein; D016227:Benzoquinones; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C494647:DNAJB1 protein, human; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C494371:HSPA8 protein, human; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D011994:Recombinant Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D053612:Janus Kinases; C085845:hop protein, Drosophila; C001277:geldanamycin