6D86

Structure of the Bovine p85a BH domain

Summary for 6D86

• Entry DOI: 10.2210/pdb6d86/pdb
• Descriptor: Phosphatidylinositol 3-kinase regulatory subunit alpha, SULFATE ION (3 entities in total)
• Functional Keywords: gap protein, signaling protein
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 2
• Total formula weight: 44010.55

Authors

Moore, S.A.,Marshall, J.D.,Anderson, D.H. (deposition date: 2018-04-25, release date: 2018-05-23, Last modification date: 2020-01-08)

Primary citation

Mellor, P.,Marshall, J.D.S.,Ruan, X.,Whitecross, D.E.,Ross, R.L.,Knowles, M.A.,Moore, S.A.,Anderson, D.H.
Patient-derived mutations within the N-terminal domains of p85 alpha impact PTEN or Rab5 binding and regulation.
Sci Rep, 8:7108-7108, 2018

PubMed Abstract: The p85α 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 p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α 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 p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activity.

PubMed: 29740032
DOI: 10.1038/s41598-018-25487-5

Experimental method

X-RAY DIFFRACTION (2.301 Å)