title: SPRY domain-containing SOCS box protein 2: crystal structure and residues critical for protein binding.
abstract: The four mammalian SPRY (a sequence repeat in dual-specificity kinase splA and ryanodine receptors) domain-containing suppressor of cytokine signalling (SOCS) box proteins (SSB-1 to -4) are characterised by a C-terminal SOCS box and a central SPRY domain. The latter is a protein interaction module found in over 1600 proteins, with more than 70 encoded in the human genome. Here we report the crystal structure of the SPRY domain of murine SSB-2 and compare it with the SSB-2 solution structure and crystal structures of other B30.2/SPRY domain-containing family proteins. The structure is a bent beta-sandwich, consisting of two seven-stranded beta-sheets wrapped around a long loop that extends from the centre strands of the inner or concave beta-sheet; it closely matches those of GUSTAVUS and SSB-4. The structure is also similar to those of two recently determined Neuralized homology repeat (NHR) domains (also known as NEUZ domains), with detailed comparisons, suggesting that the NEUZ/NHR domains form a subclass of SPRY domains. The binding site on SSB-2 for the prostate apoptosis response-4 (Par-4) protein has been mapped in finer detail using mutational analyses. Moreover, SSB-1 was shown to have a Par-4 binding surface similar to that identified for SSB-2. Structural perturbations of SSB-2 induced by mutations affecting its interaction with Par-4 and/or c-Met have been characterised by NMR. These comparisons, in conjunction with previously published dynamics data from NMR relaxation studies and coarse-grained dynamics simulation using normal mode analysis, further refine our understanding of the structural basis for protein recognition of SPRY domain-containing proteins.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Kuang
authors.forename: Shenggen
authors.initials: S
authors.lastname: Yao
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xu
authors.forename: Rowena S
authors.initials: RS
authors.lastname: Lewis
authors.forename: Andrew
authors.initials: A
authors.lastname: Low
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Willson
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Thomas J P
authors.initials: TJ
authors.lastname: Garrett
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D004268:DNA-Binding Proteins; D044462:Receptors, Proteinase-Activated; C508499:SSB-2 protein, mouse; C481942:protease-activated receptor 4, mouse