McNally Randall, Toms Angela V, Eck Michael J
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2016 May 26;11(5):e0156218. doi: 10.1371/journal.pone.0156218. eCollection 2016.
Jak-family tyrosine kinases mediate signaling from diverse cytokine receptors. Binding of Jaks to their cognate receptors is mediated by their N-terminal region, which contains FERM and SH2 domains. Here we describe the crystal structure of the FERM-SH2 region of Jak2 at 3.0Å resolution. The structure reveals that these domains and their flanking linker segments interact intimately to form an integrated structural module. The Jak2 FERM-SH2 structure closely resembles that recently described for Tyk2, another member of the Jak family. While the overall architecture and interdomain orientations are preserved between Jak2 and Tyk2, we identify residues in the putative receptor-binding groove that differ between the two and may contribute to the specificity of receptor recognition. Analysis of Jak mutations that are reported to disrupt receptor binding reveals that they lie in the hydrophobic core of the FERM domain, and are thus expected to compromise the structural integrity of the FERM-SH2 unit. Similarly, analysis of mutations in Jak3 that are associated with severe combined immunodeficiency suggests that they compromise Jak3 function by destabilizing the FERM-SH2 structure.
Jak家族酪氨酸激酶介导来自多种细胞因子受体的信号传导。Jak与它们的同源受体的结合由其N端区域介导，该区域包含FERM和SH2结构域。在此，我们描述了Jak2的FERM-SH2区域在3.0Å分辨率下的晶体结构。该结构显示这些结构域及其侧翼连接片段紧密相互作用，形成一个整合的结构模块。Jak2的FERM-SH2结构与Jak家族的另一个成员Tyk2最近描述的结构非常相似。虽然Jak2和Tyk2之间保留了整体结构和结构域间的取向，但我们确定了两个结构之间在假定的受体结合凹槽中的残基不同，这可能有助于受体识别的特异性。对据报道破坏受体结合的Jak突变的分析表明，它们位于FERM结构域的疏水核心中，因此预计会损害FERM-SH2单元的结构完整性。同样，对与严重联合免疫缺陷相关的Jak3突变的分析表明，它们通过破坏FERM-SH2结构来损害Jak3功能。
