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

Nature Structural Biology volume 6, pages 44–49 (1999)Cite this article

Abstract

The sterile alpha motif (SAM) domain is a novel protein module of ~70 amino acids that is found in a variety of signaling molecules including tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding and adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can potentially function as a protein interaction module through the ability to homo– and hetero–oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from translocation of the SAM domain of TEL to coding regions of the βPDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we describe the 2.0 Å X–ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase. The structure 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 independently folding protein module can form homophilic complexes that regulate signaling events at the membrane and in the nucleus.

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Figure 1: a, Sequence alignment of SAM domains from the Eph family of receptor tyrosine kinases and selected proteins.
Figure 2: Ribbons depictions of the EphA4 receptor SAM domain homo–dimer.
Figure 3: a,b, Molecular surface and worm representations of the SAM homodimer.
Figure 4: a, Gel filtration elution profile of wild type and single or double site mutants of the EphA4 receptor SAM domain.

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Acknowledgements

We thank N. Gale for the EphA4 receptor cDNA, C. Hogue and K. Miyata for insightful discussions and A. Chakrabartty and A. Davidson for assistance with analytical centrifugation. This work was supported by the Medical Research Council of Canada (T.P) and the National Cancer Institute of Canada (F.S). D.S. is a C. J. Martin Fellow of the National Health and Medical Research Council of Australia and T.P. is a Distinguished Scientist of the Medical Research Council of Canada.

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Authors and Affiliations

  1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 Unviersity Avenue, Toronto, M5G 1X5, Ontario, Canada

    David Stapleton, Inga Balan, Tony Pawson & Frank Sicheri

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Tony Pawson & Frank Sicheri

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  1. David Stapleton
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  2. Inga Balan
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  3. Tony Pawson
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Correspondence to Frank Sicheri.

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Stapleton, D., Balan, I., Pawson, T. et al. The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization . Nat Struct Mol Biol 6, 44–49 (1999). https://doi.org/10.1038/4917

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