7y4n
Insight into the C-terminal SH3 domain mediated binding of Drosophila Drk to Sos and Dos
Structural highlights
Function[GRAP_DROME] Adapter protein which modulates signaling mediated by several receptor tyrosine kinases such as sev and Ack (PubMed:8462097, PubMed:22615583, PubMed:8462098). Required for proper signaling by sevenless (PubMed:8462097, PubMed:8462098). May act to stimulate the ability of Sos to catalyze Ras1 activation by linking sevenless and Sos in a signaling complex (PubMed:8462097, PubMed:8462098). Required for functional and morphological integrities of the scolopidia, sensory neurons and the antennal mechanosensory and motor center (AMMC) brain neuropil (PubMed:30610177). Required for Ack-dependent suppression of apoptosis in the eye (PubMed:22615583).[1] [2] [3] [4] Publication Abstract from PubMedDrk, a Drosophila homologue of human GRB2, interacts with Sevenless (Sev) receptor via its SH2 domain, while the N- and C-terminal SH3 domains (Drk-NSH3 and Drk-CSH3, respectively) are responsible for the interaction with proline-rich motifs (PRMs) of Son of sevenless (Sos) or Daughter of Sevenless (Dos). Drk-NSH3 on its own has a conformational equilibrium between folded and unfolded states, and the folded state is stabilised by the association with a Sos-derived proline-rich peptide with PxxPxR motif. In contrast, Drk-CSH3 is supposed to bind PxxxRxxKP motifs in Dos. Aiming at clarifying the structural and functional differences between the two SH3 domains, we performed NMR studies of Drk-CSH3. The resulting solution structure and the (15)N-relaxation data showed that Drk-CSH3 consists of a stable domain. Large chemical shift perturbation was commonly found around the RT loop and the hydrophobic patch, while there were also changes that occur characteristically for Sos- or Dos-derived peptides. Sos-derived two peptides with PxxPxR motif showed stronger affinity to Drk-CSH3, indicating that the Sos PRMs can bind both N- and C-SH3 domains. Dos-derived two peptides could also bind Drk-CSH3, but with much weaker affinity, suggesting a possibility that any cooperative binding of Dos-PRMs may strengthen the Drk-Dos interaction. The NMR studies as well as the docking simulations provide valuable insights into the biological and biophysical functions of two SH3 domains in Drk. Insight into the C-terminal SH3 domain mediated binding of Drosophila Drk to Sos and Dos.,Sayeesh PM, Ikeya T, Sugasawa H, Watanabe R, Mishima M, Inomata K, Ito Y Biochem Biophys Res Commun. 2022 Oct 15;625:87-93. doi:, 10.1016/j.bbrc.2022.08.007. Epub 2022 Aug 5. PMID:35952612[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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