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Structural basis for the distinct roles of non-conserved Pro116 and conserved Tyr124 of BCH domain of yeast p50RhoGAP.
Shankar, Srihari; Chew, Ti Weng; Chichili, Vishnu Priyanka Reddy; Low, Boon Chuan; Sivaraman, J.
Afiliação
  • Shankar S; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
  • Chew TW; Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
  • Chichili VPR; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
  • Low BC; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore. dbslowbc@nus.edu.sg.
  • Sivaraman J; Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore. dbslowbc@nus.edu.sg.
Cell Mol Life Sci ; 81(1): 216, 2024 May 13.
Article em En | MEDLINE | ID: mdl-38740643
ABSTRACT
p50RhoGAP is a key protein that interacts with and downregulates the small GTPase RhoA. p50RhoGAP is a multifunctional protein containing the BNIP-2 and Cdc42GAP Homology (BCH) domain that facilitates protein-protein interactions and lipid binding and the GAP domain that regulates active RhoA population. We recently solved the structure of the BCH domain from yeast p50RhoGAP (YBCH) and showed that it maintains the adjacent GAP domain in an auto-inhibited state through the ß5 strand. Our previous WT YBCH structure shows that a unique kink at position 116 thought to be made by a proline residue between alpha helices α6 and α7 is essential for the formation of intertwined dimer from asymmetric monomers. Here we sought to establish the role and impact of this Pro116. However, the kink persists in the structure of P116A mutant YBCH domain, suggesting that the scaffold is not dictated by the proline residue at this position. We further identified Tyr124 (or Tyr188 in HBCH) as a conserved residue in the crucial ß5 strand. Extending to the human ortholog, when substituted to acidic residues, Tyr188D or Tyr188E, we observed an increase in RhoA binding and self-dimerization, indicative of a loss of inhibition of the GAP domain by the BCH domain. These results point to distinct roles and impact of the non-conserved and conserved amino acid positions in regulating the structural and functional complexity of the BCH domain.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Prolina / Proteínas Ativadoras de GTPase / Proteínas de Schizosaccharomyces pombe Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Prolina / Proteínas Ativadoras de GTPase / Proteínas de Schizosaccharomyces pombe Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article