期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 8, 页码 1982-1987出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617244114
关键词
PIK3CD; PIK3R1; HDX-MS; phosphoinositides; PI3K/AKT
资金
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada (NSERC) [2014-05218]
- Yale University and a National Heart, Lung, and Blood Institute [R00HL125668]
Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110d catalytic (PIK3CD) subunit or the ubiquitously expressed p85 alpha regulatory (PIK3R1) subunit of class IA phosphoinositide 3-kinases (PI3Ks). There are two classes of APDS: APDS1 that arises from p110 delta mutations that are analogous to oncogenic mutations found in the broadly expressed p110 alpha subunit and APDS2 that occurs from a splice mutation resulting in p85 alpha with a central deletion (Delta 434-475). As p85 regulatory subunits associate with and inhibit all class IA catalytic subunits, APDS2 mutations are expected to similarly activate p110 alpha, beta, and delta, yet APDS2 largely phenocopies APDS1 without dramatic effects outside the immune system. We have examined the molecular mechanism of activation of both classes of APDS mutations using a combination of biochemical assays and hydrogen-deuterium exchange mass spectrometry. Intriguingly, we find that an APDS2 mutation in p85 alpha leads to substantial basal activation of p110 delta (>300-fold) and disrupts inhibitory interactions from the nSH2, iSH2, and cSH2 domains of p85, whereas p110 alpha is only minimally basally activated (similar to 2-fold) when associated with mutated p85 alpha. APDS1 mutations in p110 delta (N334K, E525K, E1021K) mimic the activation mechanisms previously discovered for oncogenic mutations in p110 alpha. All APDS mutations were potently inhibited by the Food and Drug Administration approved p110 delta inhibitor idelalisib. Our results define the molecular basis of how PIK3CD and PIK3R1 mutations result in APDS and reveal a potential path to treatment for all APDS patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据