6mbw
From Proteopedia
Structure of Transcription Factor
Structural highlights
DiseaseSTA5B_HUMAN Acute promyelocytic leukemia;Laron syndrome with immunodeficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionSTA5B_HUMAN Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation.[1] [2] Publication Abstract from PubMedHyper-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 gammadelta T-cells in in vivo syngeneic transplant models, comparable to STAT5B(N642H) patient gammadelta 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. Structural and functional consequences of the STAT5B(N642H) driver mutation.,de Araujo ED, Erdogan F, Neubauer HA, Meneksedag-Erol D, Manaswiyoungkul P, Eram MS, Seo HS, Qadree AK, Israelian J, Orlova A, Suske T, Pham HTT, Boersma A, Tangermann S, Kenner L, Rulicke T, Dong A, Ravichandran M, Brown PJ, Audette GF, Rauscher S, Dhe-Paganon S, Moriggl R, Gunning PT Nat Commun. 2019 Jun 7;10(1):2517. doi: 10.1038/s41467-019-10422-7. PMID:31175292[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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