7EAL

The structure of the A20-Binding Inhibitor of NF-kB 1 in complex with di-ubiquitin

Summary for 7EAL

• Entry DOI: 10.2210/pdb7eal/pdb
• Descriptor: ubiquitin, TNFAIP3-interacting protein 1, GLYCEROL, ... (4 entities in total)
• Functional Keywords: m1-ubiquitin, nf-kb, ubiquitin-binding domain, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 85292.60

Authors

Lo, Y.C.,Lin, S.C. (deposition date: 2021-03-07, release date: 2021-07-21, Last modification date: 2023-11-29)

Primary citation

Hong, J.Y.,Lin, S.C.,Kuo, B.J.,Lo, Y.C.
Structural and Biochemical Basis for Higher-Order Assembly between A20-Binding Inhibitor of NF-kappa B 1 (ABIN1) and M1-Linked Ubiquitins.
J.Mol.Biol., 433:167116-167116, 2021

PubMed Abstract: Polyubiquitination is important in controlling NF-κB signaling. Excessive NF-κB activity has been linked to inflammatory disorders and autoimmune diseases, while ABIN1 could attenuate NF-κB activation to maintain immune homeostasis by utilizing UBAN to recognize linear (M1)-linked polyubiquitinated NF-κB activation mediators, including NEMO, IRAK1 and RIP1. PolyUb-mediated UBAN recruitment remains undetermined, since the recognition studies focused mostly on di-ubiquitin (diUb). Here we report three crystal structures of human ABIN1 UBAN (hABIN1) in complex with M1-linked diUb, triUb, and tetraUb, respectively. Notably, the hABIN1:diUb structure reveals that a diUb randomly binds one of the Ub-binding sites of the hABIN1 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 hABIN1 dimer and the C-terminal two-Ub unit to bind the secondary Ub-binding site of another hABIN1 dimer. Especially, our results suggest that two ABIN1 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.

PubMed: 34161781
DOI: 10.1016/j.jmb.2021.167116

Experimental method

X-RAY DIFFRACTION (2.5 Å)