The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4–binding residues Academic Article uri icon

abstract

  • The four mammalian SPRY domain-containing SOCS box proteins (SSB-1 to SSB-4) are characterized by a C-terminal SOCS box and a central SPRY domain. We have determined the first SPRY-domain structure, as part of SSB-2, by NMR. This domain adopts a novel fold consisting of a beta-sandwich structure formed by two four-stranded antiparallel beta-sheets with a unique topology. We demonstrate that SSB-1, SSB-2 and SSB-4, but not SSB-3, bind prostate apoptosis response protein-4 (Par-4). Mutational analysis of SSB-2 loop regions identified conserved structural determinants for its interaction with Par-4 and the hepatocyte growth factor receptor, c-Met. Mutations in analogous loop regions of pyrin and midline-1 SPRY domains have been shown to cause Mediterranean fever and Opitz syndrome, respectively. Our findings provide a template for SPRY-domain structure and an insight into the mechanism of SPRY-protein interaction.

authors

  • Masters, Seth L
  • Yao, Shenggen
  • Willson, Tracy A
  • Zhang, Jian-Guo
  • Palmer, Kirsten R
  • Smith, Brian J
  • Babon, Jeffrey J
  • Nicola, Nicos A
  • Norton, Raymond S
  • Nicholson, Sandra E

publication date

  • January 2006

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