5yqg
From Proteopedia
The structure of 14-3-3 and pNumb peptide
Structural highlights
Function[1433F_MOUSE] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1 (By similarity). [NUMB_MOUSE] Plays a role in the process of neurogenesis. Required throughout embryonic neurogenesis to maintain neural progenitor cells, also called radial glial cells (RGCs), by allowing their daughter cells to choose progenitor over neuronal cell fate. Not required for the proliferation of neural progenitor cells before the onset of neurogenesis. Also involved postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity. May also mediate local repair of brain ventricular wall damage.[1] [2] [3] [4] Publication Abstract from PubMedTraffic of cargo across membranes helps establish, maintain, and reorganize distinct cellular compartments and is fundamental to many metabolic processes. The cargo-selective endocytic adaptor Numb participates in clathrin-dependent endocytosis by attaching cargoes to the clathrin adaptor alpha-adaptin. The phosphorylation of Numb at Ser(265) and Ser(284) recruits the regulatory protein 14-3-3, accompanied by the dissociation of Numb from alpha-adaptin and Numb's translocation from the cortical membrane to the cytosol. However, the molecular mechanisms underlying the Numb-alpha-adaptin interaction and its regulation by Numb phosphorylation and 14-3-3 recruitment remain poorly understood. Here, biochemical and structural analyses of the Numb.14-3-3 complex revealed that Numb phosphorylation at both Ser(265) and Ser(284) is required for Numb's efficient interaction with 14-3-3. We also discovered that an RQFRF motif surrounding Ser(265) in Numb functions together with the canonical C-terminal DPF motif, required for Numb's interaction with alpha-adaptin, to form a stable complex with alpha-adaptin. Of note, we provide evidence that the phosphorylation-induced binding of 14-3-3 to Numb directly competes with the binding of alpha-adaptin to Numb. Our findings suggest a potential mechanism governing the dynamic assembly of Numb with alpha-adaptin or 14-3-3. This dual-site recognition of Numb by alpha-adaptin may have implications for other alpha-adaptin targets. We propose that the newly identified alpha-adaptin-binding site surrounding Ser(265) in Numb functions as a triggering mechanism for the dynamic dissociation of the Numb.alpha-adaptin complex. Structural determinants controlling 14-3-3 recruitment to the endocytic adaptor Numb and dissociation of the Numb.alpha-adaptin complex.,Chen X, Liu Z, Shan Z, Yao W, Gu A, Wen W J Biol Chem. 2018 Mar 16;293(11):4149-4158. doi: 10.1074/jbc.RA117.000897. Epub, 2018 Jan 30. PMID:29382713[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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