Crystal Structure of the FERM-SH2 Module of Human Jak2.
Crystal Structure of the FERM-SH2 Module of Human Jak2.
复制标题
人类JAK2的FERM-SH2模块的晶体结构。
DOI：
10.1371/journal.pone.0156218
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Eck MJ
中科院分区：
文献类型：
--
作者：
McNally R;Toms AV;Eck MJ
Jak 家族酪氨酸激酶介导多种细胞因子受体的信号传导。 Jaks 与其同源受体的结合是由其 N 末端区域介导的，该区域包含 FERM 和 SH2 结构域。在这里，我们以 3.0Å 分辨率描述了 Jak2 FERM-SH2 区域的晶体结构。该结构揭示了这些结构域及其侧翼连接片段密切相互作用，形成一个集成的结构模块。 Jak2 FERM-SH2 结构与最近描述的 Jak 家族另一个成员 Tyk2 的结构非常相似。虽然 Jak2 和 Tyk2 之间保留了整体结构和域间方向，但我们在假定的受体结合沟中发现了两者之间不同的残基，这些残基可能有助于受体识别的特异性。据报道，Jak 突变会破坏受体结合，分析表明它们位于 FERM 结构域的疏水核心，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 结构的稳定性来损害 Jak3 功能。
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.