Hong JY, Lin SC, Kuo BJ, Lo YC

Polyubiquitination is important in controlling NF-?B signaling. Excessive NF-?B activity has been linked to inflammatory disorders and autoimmune diseases, while ABIN1 could attenuate NF-?B activation to maintain immune homeostasis by utilizing UBAN to recognize linear (M1)-linked polyubiquitinated NF-?B activation mediators, including NEMO, IRAK1 and RIP1. PolyUb-mediated UBAN recruitment remains undetermined, ...

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since the recognition studies focused mostly on di-ubiquitin (diUb). Here we report three crystal structures of human ABIN1 UBAN (hABIN1UBAN) in complex with M1-linked diUb, triUb, and tetraUb, respectively. Notably, the hABIN1UBAN:diUb structure reveals that a diUb randomly binds one of the Ub-binding sites of the hABIN1UBAN dimer and leaves the other site vacant. Together with the ITC and gel-filtration analyses, we found that M1-triUb and M1-tetraUb adopt two unique conformations, instead of an elongated one, and they preferentially use the N-terminal two-Ub unit to bind the primary Ub-binding site of a hABIN1UBAN dimer and the C-terminal two-Ub unit to bind the secondary Ub-binding site of another hABIN1UBAN dimer. Especially, our results suggest that two ABIN1UBAN dimers cooperatively bind two UBAN-binding units of a tetraUb or vice versa. Since the UBAN family members share a conserved diUb-binding mode, our results suggest that M1-polyUb modification allows multiple copies of the two-tandem Ub unit to simultaneously coordinate multiple and/or different binding partners to increase their local concentrations and to facilitate the formation of a large signaling complex. Our study provides a structural-functional glimpse of M1-polyUb as a multiple-molecule binding platform to exert its intrinsic structural plasticity in mediating cellular signaling.

Date: Dec. 03, 2020

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