6D82

Structure of the Bovine p85a BH domain

6D82 の概要

• エントリーDOI: 10.2210/pdb6d82/pdb
• 分子名称: Phosphatidylinositol 3-kinase regulatory subunit alpha, SULFATE ION (3 entities in total)
• 機能のキーワード: gap protein, signaling protein
• 由来する生物種: Bos taurus (Bovine)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44106.61

構造登録者

Moore, S.A.,Marshall, J.D.,Anderson, D.H. (登録日: 2018-04-25, 公開日: 2018-05-23, 最終更新日: 2020-01-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.407 Å)