Cargando…

Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal

Protein poly(ADP-ribosyl)ation (PARylation) plays a role in diverse cellular processes such as DNA repair, transcription, Wnt signaling, and cell death(1–6). Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several critical regulatory prot...

Descripción completa

Detalles Bibliográficos
Autores principales: DaRosa, Paul A., Wang, Zhizhi, Jiang, Xiaomo, Pruneda, Jonathan N., Cong, Feng, Klevit, Rachel E., Xu, Wenqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289021/
https://www.ncbi.nlm.nih.gov/pubmed/25327252
http://dx.doi.org/10.1038/nature13826
_version_ 1782352042774233088
author DaRosa, Paul A.
Wang, Zhizhi
Jiang, Xiaomo
Pruneda, Jonathan N.
Cong, Feng
Klevit, Rachel E.
Xu, Wenqing
author_facet DaRosa, Paul A.
Wang, Zhizhi
Jiang, Xiaomo
Pruneda, Jonathan N.
Cong, Feng
Klevit, Rachel E.
Xu, Wenqing
author_sort DaRosa, Paul A.
collection PubMed
description Protein poly(ADP-ribosyl)ation (PARylation) plays a role in diverse cellular processes such as DNA repair, transcription, Wnt signaling, and cell death(1–6). Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several critical regulatory proteins, including Axin and 3BP2 (refs 7–9). The RING-type E3 ubiquitin ligase RNF146 (a.k.a. Iduna) is responsible for PARylation-dependent ubiquitination (PARdU)(10–12). Here we provide a structural basis for RNF146 catalyzed PARdU and how PARdU specificity is achieved. First, we show that iso-ADPr, the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one. In the absence of PAR, the RING domain is unable to efficiently bind and activate an E2. Binding of PAR/iso-ADPr induces a major conformational change that creates a functional RING structure. Thus RNF146 represents a new mechanistic class of RING E3 ligases whose activities are regulated by non-covalent ligand binding, which may provide a template for designing inducible protein-degradation systems. Second, we found that RNF146 directly interacts with the PAR polymerase tankyrase (TNKS). Disruption of the RNF146/TNKS interaction inhibits turnover of the substrate Axin in cells. Thus, both substrate PARylation and PARdU are catalyzed by enzymes within the same protein complex, and PARdU substrate specificity may be primarily determined by the substrate-TNKS interaction. We propose that maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146-TNKS complex, which in turn regulates the homeostasis of PARdU activity in the cell.
format Online
Article
Text
id pubmed-4289021
institution National Center for Biotechnology Information
language English
publishDate 2014
record_format MEDLINE/PubMed
spelling pubmed-42890212015-07-08 Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal DaRosa, Paul A. Wang, Zhizhi Jiang, Xiaomo Pruneda, Jonathan N. Cong, Feng Klevit, Rachel E. Xu, Wenqing Nature Article Protein poly(ADP-ribosyl)ation (PARylation) plays a role in diverse cellular processes such as DNA repair, transcription, Wnt signaling, and cell death(1–6). Recent studies have shown that PARylation can serve as a signal for the polyubiquitination and degradation of several critical regulatory proteins, including Axin and 3BP2 (refs 7–9). The RING-type E3 ubiquitin ligase RNF146 (a.k.a. Iduna) is responsible for PARylation-dependent ubiquitination (PARdU)(10–12). Here we provide a structural basis for RNF146 catalyzed PARdU and how PARdU specificity is achieved. First, we show that iso-ADPr, the smallest internal poly(ADP-ribose) (PAR) structural unit, binds between the WWE and RING domains of RNF146 and functions as an allosteric signal that switches the RING domain from a catalytically inactive state to an active one. In the absence of PAR, the RING domain is unable to efficiently bind and activate an E2. Binding of PAR/iso-ADPr induces a major conformational change that creates a functional RING structure. Thus RNF146 represents a new mechanistic class of RING E3 ligases whose activities are regulated by non-covalent ligand binding, which may provide a template for designing inducible protein-degradation systems. Second, we found that RNF146 directly interacts with the PAR polymerase tankyrase (TNKS). Disruption of the RNF146/TNKS interaction inhibits turnover of the substrate Axin in cells. Thus, both substrate PARylation and PARdU are catalyzed by enzymes within the same protein complex, and PARdU substrate specificity may be primarily determined by the substrate-TNKS interaction. We propose that maintenance of unliganded RNF146 in an inactive state may serve to maintain the stability of the RNF146-TNKS complex, which in turn regulates the homeostasis of PARdU activity in the cell. 2014-10-19 2015-01-08 /pmc/articles/PMC4289021/ /pubmed/25327252 http://dx.doi.org/10.1038/nature13826 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
DaRosa, Paul A.
Wang, Zhizhi
Jiang, Xiaomo
Pruneda, Jonathan N.
Cong, Feng
Klevit, Rachel E.
Xu, Wenqing
Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title_full Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title_fullStr Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title_full_unstemmed Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title_short Allosteric Activation of the RNF146 Ubiquitin Ligase by a Poly(ADP-ribosyl)ation Signal
title_sort allosteric activation of the rnf146 ubiquitin ligase by a poly(adp-ribosyl)ation signal
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289021/
https://www.ncbi.nlm.nih.gov/pubmed/25327252
http://dx.doi.org/10.1038/nature13826
work_keys_str_mv AT darosapaula allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT wangzhizhi allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT jiangxiaomo allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT prunedajonathann allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT congfeng allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT klevitrachele allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal
AT xuwenqing allostericactivationofthernf146ubiquitinligasebyapolyadpribosylationsignal