Structural and functional consequences of the STAT5BN642H driver mutation

被引：62

作者：

de Araujo, Elvin D. ^{[1
,2
]}

Erdogan, Fettah ^{[1
,2
]}

Neubauer, Heidi A. ^{[3
,4
]}

Meneksedag-Erol, Deniz ^{[1
,5
]}

Manaswiyoungkul, Pimyupa ^{[1
,2
]}

Eram, Mohammad S. ^{[6
]}

Seo, Hyuk-Soo ^{[7
,8
]}

Qadree, Abdul K. ^{[1
,2
]}

Israelian, Johan ^{[1
,2
]}

Orlova, Anna ^{[3
,4
]}

Suske, Tobias ^{[3
]}

Pham, Ha T. T. ^{[3
,4
]}

Boersma, Auke ^{[9
]}

Tangermann, Simone ^{[10
]}

Kenner, Lukas ^{[4
,10
,11
]}

Ruelicke, Thomas ^{[9
]}

Dong, Aiping ^{[12
]}

Ravichandran, Manimekalai ^{[12
]}

Brown, Peter J. ^{[12
]}

Audette, Gerald F. ^{[13
]}

Rauscher, Sarah ^{[1
,2
,5
]}

Dhe-Paganon, Sirano ^{[7
,8
]}

Moriggl, Richard ^{[3
,4
,14
]}

Gunning, Patrick T. ^{[1
,2
]}

机构：

[1] Univ Toronto Mississauga, Dept Chem & Phys Sci, 3359 Mississauga Rd North, Mississauga, ON L5L 1C6, Canada

[2] Univ Toronto, Dept Chem, 80 St George St, Toronto, ON M5S 3H6, Canada

[3] Univ Vet Med Vienna, Inst Anim Breeding & Genet, A-1210 Vienna, Austria

[4] Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria

[5] Univ Toronto, Dept Phys, 60 St George St, Toronto, ON M5S 1A7, Canada

[6] Univ Toronto Mississauga, Dalriada Drug Discovery, 3359 Mississauga Rd North, Mississauga, ON L5L 1C6, Canada

[7] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[8] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 450 Brookline Ave, Boston, MA 02215 USA

[9] Univ Vet Med Vienna, Inst Lab Anim Sci, A-1210 Vienna, Austria

[10] Univ Vet Med Vienna, Unit Lab Anim Pathol, A-1210 Vienna, Austria

[11] Med Univ Vienna, Dept Expt & Lab Anim Pathol, Clin Inst Pathol, A-1090 Vienna, Austria

[12] Univ Toronto, Struct Genom Consortium, 101 Coll St, Toronto, ON M5G 1L7, Canada

[13] York Univ, Dept Chem, 327C Life Sci Bldg,4700 Keele St, Toronto, ON M3J 1P3, Canada

[14] Med Univ Vienna, A-1090 Vienna, Austria

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院; 加拿大创新基金会; 奥地利科学基金会;

关键词：

JAK-STAT PATHWAY; ACUTE LYMPHOBLASTIC-LEUKEMIA; MOLECULAR-DYNAMICS; N642H MUTATION; CELL; IDENTIFICATION; REFINEMENT; EXPRESSION; SYSTEM; DOMAIN;

D O I：

10.1038/s41467-019-10422-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5B(N642H), a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5B(N642H) in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5B(N642H)-driven transformation of yo T-cells in in vivo syngeneic transplant models, comparable to STAT5B(N642H) patient yo T-cell entities. Importantly, we present human STAT5B and STAT5B(N642H) crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5B(N642H) can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5B(N642H), conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5B(N642H) activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.

引用

页数：15

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