The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization

The sterile alpha motif (SAM) domain is a novel protein module of similar t o 70 amino acids that is found in a variety of signaling molecules includin g tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding an d adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can pote ntially function as a protein interaction module through the ability to hom o- and hetero-oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from transloc ation of the SAM domain of TEL to coding regions of the beta PDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we descri be the 2.0 Angstrom X-ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase, The structu re reveals a mode of dimerization that we predict is shared amongst the SAM domains of the Eph receptor tyrosine kinases and possibly other SAM domain containing proteins, These data indicate a mechanism through which an inde pendently folding protein module can form hemophilic complexes that regulat e signaling events at the membrane and in the nucleus.