McNally, RandallToms, Angela V.Eck, Michael2016-07-142016McNally, Randall, Angela V. Toms, and Michael J. Eck. 2016. “Crystal Structure of the FERM-SH2 Module of Human Jak2.” PLoS ONE 11 (5): e0156218. doi:10.1371/journal.pone.0156218. http://dx.doi.org/10.1371/journal.pone.0156218.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662220Jak-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.en-USBiology and life sciencesBiochemistryProteinsProtein domainsSH2 domainPhysical SciencesPhysicsCondensed Matter PhysicsSolid State PhysicsCrystallographyCrystal StructureBiology and Life SciencesImmunologyImmune System ProteinsImmune ReceptorsCytokine ReceptorsMedicine and Health SciencesCell BiologySignal TransductionSalt BridgesChemistryElectrochemistryChemical PhysicsMolecular StructureEnzymologyEnzymesProtein KinasesTyrosine KinasesPhysical ChemistryChemical BondingHydrogen BondingGeneticsMutationPoint MutationJournal Article2016-07-1410.1371/journal.pone.0156218