Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases

被引：77

作者：

Toms, Angela V. ^{[1
,2
]}

Deshpande, Anagha ^{[3
,4
]}

McNally, Randall ^{[1
,2
]}

Jeong, Youngjee ^{[1
]}

Rogers, Julia M. ^{[2
,5
]}

Kim, Chae Un ^{[6
]}

Gruner, Sol M. ^{[6
,7
]}

Ficarro, Scott B. ^{[1
,2
,8
]}

Marto, Jarrod A. ^{[1
,2
,8
]}

Sattler, Martin ^{[3
,4
]}

Griffin, James D. ^{[3
,4
]}

Eck, Michael J. ^{[1
,2
]}

机构：

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

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

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

[4] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[5] Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA

[6] Cornell Univ, Cornell High Energy Synchrotron Source, Ithaca, NY 14853 USA

[7] Cornell Univ, Dept Phys, Ithaca, NY 14853 USA

[8] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2013年 / 20卷 / 10期

基金：

美国国家卫生研究院;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; POLYCYTHEMIA-VERA; TYROSINE KINASE; PROTEIN-KINASE; MYELOPROLIFERATIVE DISORDERS; JANUS KINASES; MUTATIONS; INHIBITORS; JAK2V617F; RECEPTOR;

D O I：

10.1038/nsmb.2673

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：

The V617F mutation in the Jak2 pseudokinase domain causes myeloproliferative neoplasms, and the equivalent mutation in Jak1 (V658F) is found in T-cell leukemias. Crystal structures of wild-type and V658F-mutant human Jak1 pseudokinase reveal a conformational switch that remodels a linker segment encoded by exon 12, which is also a site of mutations in Jak2. This switch is required for V617F-mediated Jak2 activation and possibly for physiologic Jak activation.

引用

页码：1221 / +

页数：4

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