1] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nat Struct Mol Biol. 2013 Oct;20(10):1221-3. doi: 10.1038/nsmb.2673. Epub 2013 Sep 8.
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.
Jak2 假激酶结构域中的 V617F 突变可导致骨髓增殖性肿瘤，而 Jak1 中的等效突变（V658F）则存在于 T 细胞白血病中。野生型和 V658F 突变型人 Jak1 假激酶的晶体结构揭示了一种构象开关，该开关重塑了由外显子 12 编码的连接子片段，该片段也是 Jak2 突变的位点。该开关对于 V617F 介导的 Jak2 激活以及可能的生理 Jak 激活是必需的。
