Crystal Structure of the FERM-SH2 Module of Human Jak2

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（Jak-family tyrosine kinases）介导多种细胞因子受体的信号转导。Jaks与其同源受体的结合由其N端区域介导，该区域包含FERM结构域与SH2结构域。本研究解析了分辨率为3.0埃的Jak2 FERM-SH2区域晶体结构。该结构显示，这两个结构域及其侧翼连接区段紧密相互作用，形成一个整合式结构模块。Jak2的FERM-SH2结构与另一个Jak家族成员Tyk2近期解析的结构高度相似。尽管Jak2与Tyk2的整体架构及域间取向保持一致，但本研究鉴定出二者在推定的受体结合凹槽中存在差异的残基，这些残基可能参与受体识别的特异性调控。对已报道的会破坏受体结合的Jak突变体的分析显示，这些突变位点位于FERM结构域的疏水核心，因此推测它们会损害FERM-SH2单元的结构完整性。同样，对与重症联合免疫缺陷相关的Jak3突变体的分析表明，这些突变通过破坏FERM-SH2结构的稳定性来损害Jak3的功能。