Structural highlights
Publication Abstract from PubMedTo investigate the range of autoinhibitory mechanisms used by tyrosine kinase domains (TKDs) from the insulin receptor family of receptor tyrosine kinases, we determined crystal structures of TKDs from TrkA (nerve growth factor receptor) and Ror2 (an unconventional Wnt receptor). TrkA autoinhibition closely resembles that seen for insulin receptor, relying on projection of an activation loop tyrosine into the substrate binding site and occlusion of the ATP binding site by the activation loop. Ror2 employs similar mechanisms, but the unusual replacement of the phenylalanine in its Asp-Phe-Gly motif with leucine necessitates occlusion of the ATP-binding site by other means. The unusual Asp-Leu-Gly motif in Ror2 is displaced compared with other inactive kinases, allowing the activation loop to interact directly with the TKDs alphaC helix, in another mode of autoinhibition that is characteristic of the other extreme of this receptor family ALK and Met. These findings provide insight into the expected range of activating mutations in these TKDs in cancer. We also describe a symmetric dimer of the inactive TrkA TKD resembling that found in other receptor tyrosine kinases - possibly reflecting an arrangement of kinase domains in a pre-formed TrkA dimer. Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family.,Artim SC, Mendrola JM, Lemmon MA Biochem J. 2012 Sep 20. PMID:22992069[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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