6d82 | pdb_00006d82

Structure of the Bovine p85a BH domain

spinqualitylabelsall models 6d82, resolution 2.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d82 is a 2 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.407Å Ligands: CSO, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function P85A_BOVIN Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (By similarity). Publication Abstract from PubMed The p85alpha protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85alpha mutations located within the N-terminal domains of p85alpha previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85alpha mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85alpha mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85alpha mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85alpha towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85alpha BH domain mutants (E137K, E217K, R262T E297K) for bovine p85alpha BH and found that the mutations did not alter the overall domain structure. Thus, several p85alpha mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85alpha BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activity. Patient-derived mutations within the N-terminal domains of p85alpha impact PTEN or Rab5 binding and regulation.,Mellor P, Marshall JDS, Ruan X, Whitecross DE, Ross RL, Knowles MA, Moore SA, Anderson DH Sci Rep. 2018 May 8;8(1):7108. doi: 10.1038/s41598-018-25487-5. PMID:29740032 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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