Stress-inducible phosphoprotein 1 (STIP1) is a cellular co-chaperone, which regulates heat-shock protein 70 (Hsp70) and Hsp90 activity during client protein folding. Members of the S100 family of dimeric calcium-binding proteins have been found to inhibit Hsp association with STIP1 through binding of STIP1 tetratricopeptide repeat (TPR) domains, possibly regulating the chaperone cycle. Here, we investigated the molecular basis of S100A1 binding to STIP1. We show that three S100A1 dimers associate with one molecule of STIP1 in a calcium-dependent manner. Isothermal titration calorimetry revealed that individual STIP1 TPR domains, TPR1, TPR2A and TPR2B, bind a single S100A1 dimer with significantly different affinities and that the TPR2B domain possesses the highest affinity for S100A1. S100A1 bound each TPR domain through a common binding interface composed of α-helices III and IV of each S100A1 subunit, which is only accessible following a large conformational change in S100A1 upon calcium binding. The TPR2B-binding site for S100A1 was predominately mapped to the C-terminal α-helix of TPR2B, where it is inserted into the hydrophobic cleft of an S100A1 dimer, suggesting a novel binding mechanism. Our data present the structural basis behind STIP1 and S100A1 complex formation, and provide novel insights into TPR module-containing proteins and S100 family member complexes.
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Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. ANP, which maintains cardiovascular homeostasis via its diuretic, natriuretic and hypotensive effects, acts through its receptor, GC-A. In this issue of the Biochemical Journal, Miura et al. (pages 1897–1918) established mouse immortalized endothelial cells stably expressing GC-A (SVEC/GC-A) and found that ANP promotes cell spreading and endothelial barrier function via regulation of CCM2, an adaptor protein involved in the pathogenesis of cerebral cavernous malformations, a neurovascular disease characterized by dysfunction of the endothelial barrier. The image shows ANP promotes co-localization of GC-A (green) and CCM2 (red) at membrane ruffles in SVEC/GC-A. Image kindly provided by Koichi Miura
Molecular basis for the interaction between stress-inducible phosphoprotein 1 (STIP1) and S100A1
Andrzej Maciejewski, Vania F. Prado, Marco A.M. Prado, Wing-Yiu Choy; Molecular basis for the interaction between stress-inducible phosphoprotein 1 (STIP1) and S100A1. Biochem J 1 June 2017; 474 (11): 1853–1866. doi: https://doi.org/10.1042/BCJ20161055
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