The structural basis of PTEN regulation by multi-site phosphorylation

被引：28

作者：

Dempsey, Daniel R. ^{[1
,2
]}

Viennet, Thibault ^{[2
,3
]}

Iwase, Reina ^{[1
,2
]}

Park, Eunyoung ^{[2
,3
]}

Henriquez, Stephanie ^{[4
]}

Chen, Zan ^{[4
]}

Jeliazkov, Jeliazko R. ^{[5
,6
]}

Palanski, Brad A. ^{[1
,2
]}

Phan, Kim L. ^{[7
,8
,9
]}

Coote, Paul ^{[2
,3
]}

Gray, Jeffrey J. ^{[5
,6
]}

Eck, Michael J. ^{[2
,3
]}

Gabelli, Sandra B. ^{[7
,8
,9
]}

Arthanari, Haribabu ^{[2
,3
]}

Cole, Philip A. ^{[1
,2
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA

[5] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA

[6] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA

[7] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA

[8] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[9] Johns Hopkins Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2021年 / 28卷 / 10期

关键词：

VOLTAGE-SENSING PHOSPHATASE; TENSIN-HOMOLOG PTEN; TUMOR-SUPPRESSOR PHOSPHATASE; SUBSTRATE-SPECIFICITY; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; WEB SERVER; BINDING; ACTIVATION; MECHANISM;

D O I：

10.1038/s41594-021-00668-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

PTEN is a key cell signaling lipid phosphatase that is regulated by C-terminal phosphorylation. Biophysical methods were used to illuminate the structural basis for PTEN regulation, which involves a dynamic N-terminal helix that influences catalysis. Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP3) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal alpha-helix and show that it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN's cellular functions.

引用

页码：858 / +

页数：27

共 66 条

[1] Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3β [J].