Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) is an HSP90 co-chaperone required for the maturation of several essential multiprotein complexes, including RNA polymerase II, small nucleolar ribonucleoproteins, and PIKK complexes such as mTORC1 and ATR-ATRIP. RUVBL1-RUVBL2 AAA-ATPases are also primary components of other essential complexes such as INO80 and Tip60 remodelers. Despite recent efforts, the molecular mechanisms regulating RUVBL1-RUVBL2 in these complexes remain elusive. Here, we report cryo-EM structures of R2TP and show how access to the nucleotide-binding site of RUVBL2 is coupled to binding of the client recruitment component of R2TP (PIH1D1) to its DII domain. This interaction induces conformational rearrangements that lead to the destabilization of an N-terminal segment of RUVBL2 that acts as a gatekeeper to nucleotide exchange. This mechanism couples protein-induced motions of the DII domains with accessibility of the nucleotide-binding site in RUVBL1-RUVBL2, and it is likely a general mechanism shared with other RUVBL1-RUVBL2-containing complexes.
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PMID:Structural mechanism for regulation of the AAA-ATPases RUVBL1-RUVBL2 in the R2TP co-chaperone revealed by cryo-EM. 3104 1

The Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex is a co-chaperone complex that works together with HSP90 in the activation and assembly of several macromolecular complexes, including RNA polymerase II (Pol II) and complexes of the phosphatidylinositol-3-kinase-like family of kinases (PIKKs), such as mTORC1 and ATR/ATRIP. R2TP is made of four subunits: RuvB-like protein 1 (RUVBL1) and RuvB-like 2 (RUVBL2) AAA-type ATPases, RNA polymerase II-associated protein 3 (RPAP3), and the Protein interacting with Hsp90 1 (PIH1) domain-containing protein 1 (PIH1D1). R2TP associates with other proteins as part of a complex co-chaperone machinery involved in the assembly and maturation of a growing list of macromolecular complexes. Recent progress in the structural characterization of R2TP has revealed an alpha-helical domain at the C-terminus of RPAP3 that is essential to bring the RUVBL1 and RUVBL2 ATPases to R2TP. The RPAP3 C-terminal domain interacts directly with RUVBL2 and it is also known as RUVBL2-binding domain (RBD). Several human proteins contain a region homologous to the RPAP3 C-terminal domain, and some are capable of assembling R2TP-like complexes, which could have specialized functions. Only the RUVBL1-RUVBL2 ATPase complex and a protein containing an RPAP3 C-terminal-like domain are found in all R2TP and R2TP-like complexes. Therefore, the RPAP3 C-terminal domain is one of few components essential for the formation of all R2TP and R2TP-like co-chaperone complexes.
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PMID:RPAP3 C-Terminal Domain: A Conserved Domain for the Assembly of R2TP Co-Chaperone Complexes. 3238 3