SPRED2 (NMR): Human sprouty-related, EVH1 domain containing 2
PDB Code: 2JP2
SPRED (Sprouty- related EVH1 domain-containing) proteins are a novel family of membrane-associated suppressors of growth factor-induced Ras/ERK/MAPK activation. The founding member of this family was the Drosophila orthologe AE33, which was proposed to be involved in photoreceptor cell development. Following this, three murine and human Spreds (Spred-1, Spred-2, Spred-3), two Xenopus Spreds and Eve-3, an alternative splice variant of Spred-3, were described. Spred family members contain an N-terminal EVH1 (Ena/VASP homology 1) domain, a central c-Kit binding domain (KBD), and a C-terminal Sprouty-like cysteine-rich domain (SPR-domain). In adult mammals, Spred-1 is expressed predominantly in brain and, to a lower level, almost ubiquitously. In foetal tissues, Spred-1 is found in brain, heart and other tissues, suggesting a possible role in development. In contrast, Spred-2 expression is rare in foetal tissues but almost ubiquitous in adults. High levels of Spred-2 expression are seen in neural tissues and different glandular epithelial cells. Spred-3 was only detected in brain, whereas its alternative splicing variant Eve-3, was limited to the developed liver. Mechanistically, Spred proteins appear to inhibit early steps of MAP kinase activation by enhancing the interaction of Ras with Raf, thereby preventing Raf activation via phosphorylation . Functional data using C-terminally truncated mutants suggest that suppression of MAP kinase activation by Spred proteins is mediated by their N-terminal EVH1 domains. The specific function of the Spred EVH1 domain in this process thus appears to be in the recruitment of the Spred proteins to sites where inhibition of the Ras/ERK/MAPK pathway is necessary.
Based on sequence conservation, four different subclasses of EVH1 domains (also referred to as WH1 domains) have been identified to date, with the Spred EVH1 domains belonging to the most recently identified, fourth class. High resolution structures are available for representatives of all classes, but until now no structural information was available for a human member of the fourth class. Here, in collaboration with Prof. U. Walter and Dr. Thomas Jarchau at the University of Wuerzburg, and Hartmut Oschkinat at FMP, Berlin, we have expressed and purified isotopically enriched 13C, 15N-labelled samples of the human Spred2 EVH1 domain and have solved its three dimensional solution structure by NMR spectroscopy.
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