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Structural determinants controlling 14-3-3 recruitment to the endocytic adaptor Numb and dissociation of the Numb·?-adaptin complex.


ABSTRACT: Traffic 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 ?-adaptin. The phosphorylation of Numb at Ser265 and Ser284 recruits the regulatory protein 14-3-3, accompanied by the dissociation of Numb from ?-adaptin and Numb's translocation from the cortical membrane to the cytosol. However, the molecular mechanisms underlying the Numb-?-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 Ser265 and Ser284 is required for Numb's efficient interaction with 14-3-3. We also discovered that an RQFRF motif surrounding Ser265 in Numb functions together with the canonical C-terminal DPF motif, required for Numb's interaction with ?-adaptin, to form a stable complex with ?-adaptin. Of note, we provide evidence that the phosphorylation-induced binding of 14-3-3 to Numb directly competes with the binding of ?-adaptin to Numb. Our findings suggest a potential mechanism governing the dynamic assembly of Numb with ?-adaptin or 14-3-3. This dual-site recognition of Numb by ?-adaptin may have implications for other ?-adaptin targets. We propose that the newly identified ?-adaptin-binding site surrounding Ser265 in Numb functions as a triggering mechanism for the dynamic dissociation of the Numb·?-adaptin complex.

SUBMITTER: Chen X 

PROVIDER: S-EPMC5857998 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Structural determinants controlling 14-3-3 recruitment to the endocytic adaptor Numb and dissociation of the Numb·α-adaptin complex.

Chen Xing X   Liu Ziheng Z   Shan Zelin Z   Yao Weiyi W   Gu Aihong A   Wen Wenyu W  

The Journal of biological chemistry 20180130 11


Traffic 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 α-adaptin. The phosphorylation of Numb at Ser<sup>265</sup> and Ser<sup>284</sup> recruits the regulatory protein 14-3-3, accompanied by the dissociation of Numb from α-adaptin and Numb's translocation from the  ...[more]

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