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The structure of the A20-binding inhibitor of NF-kB 1 in complex with tetra-ubiquitin
Structural highlights
FunctionUBC_HUMAN Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] Publication Abstract from PubMedPolyubiquitination is important in controlling NF-kappaB signaling. Excessive NF-kappaB activity has been linked to inflammatory disorders and autoimmune diseases, while ABIN1 could attenuate NF-kappaB activation to maintain immune homeostasis by utilizing UBAN to recognize linear (M1)-linked polyubiquitinated NF-kappaB 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(UBAN)) in complex with M1-linked diUb, triUb, and tetraUb, respectively. Notably, the hABIN1(UBAN):diUb structure reveals that a diUb randomly binds one of the Ub-binding sites of the hABIN1(UBAN) 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(UBAN) dimer and the C-terminal two-Ub unit to bind the secondary Ub-binding site of another hABIN1(UBAN) dimer. Especially, our results suggest that two ABIN1(UBAN) 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. Structural and Biochemical Basis for Higher-Order Assembly between A20-Binding Inhibitor of NF-kappaB 1 (ABIN1) and M1-Linked Ubiquitins.,Hong JY, Lin SC, Kuo BJ, Lo YC J Mol Biol. 2021 Sep 3;433(18):167116. doi: 10.1016/j.jmb.2021.167116. Epub 2021 , Jun 20. PMID:34161781[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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