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Dynamics of the SPRY domain–containing SOCS box protein 2: Flexibility of key functional loops

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia
² Centre for Molecular Simulation, Swinburne University of Technology, Hawthorn 3122, Victoria, Australia
³ Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia

(RECEIVED August 1, 2006; FINAL REVISION September 11, 2006; ACCEPTED September 12, 2006)

The SPRY domain was identified originally as a sequence repeat in the dual-specificity kinase splA and ryanodine receptors and subsequently found in many other distinct proteins, including more than 70 encoded in the human genome. It is a subdomain of the B30.2/SPRY domain and is believed to function as a protein–protein interaction module. Three-dimensional structures of several B30.2/SPRY domain–containing proteins have been reported recently: murine SSB-2 in solution by NMR spectroscopy, a Drosophila SSB (GUSTAVUS), and human PRYSPRY protein by X-ray crystallography. The three structures share a core of two antiparallel -sheets for the B30.2/SPRY domain but show differences located mainly at one end of the -sandwich. Analysis of SSB-2 residues required for interactions with its intracellular ligands has provided insights into B30.2/SPRY binding specificity and identified loop residues critical for the function of this domain. We have investigated the backbone dynamics of SSB-2 by means of Modelfree analysis of its backbone ¹⁵N relaxation parameters and carried out coarse-grained dynamics simulation of B30.2/SPRY domain–containing proteins using normal mode analysis. Translational self-diffusion coefficients of SSB-2 measured using pulsed field gradient NMR were used to confirm the monomeric state of SSB-2 in solution. These results, together with previously reported amide exchange data, highlight the underlying flexibility of the loop regions of B30.2/SPRY domain–containing proteins that have been shown to be important for protein–protein interactions. The underlying flexibility of certain regions of the B30.2/SPRY domain–containing proteins may also contribute to some apparent structural differences observed between GUSTAVUS or PRYSPRY and SSB-2.

Keywords: backbone dynamics; conformational exchange; normal mode analysis; NMR; ¹⁵N relaxation; SOCS protein; B30.2/SPRY domain; translational diffusion

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