7M4M

Crystal structure of RBR E3 ligase RNF216 with ubiquitin

Summary for 7M4M

• Entry DOI: 10.2210/pdb7m4m/pdb
• Descriptor: E3 ubiquitin-protein ligase RNF216, Ubiquitin, ZINC ION, ... (5 entities in total)
• Functional Keywords: e3 ligase, rbr, ubiquitin, enzyme, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 81252.32

Authors

Cotton, T.R.,Lechtenberg, B.C. (deposition date: 2021-03-21, release date: 2022-01-05, Last modification date: 2024-04-03)

Primary citation

Cotton, T.R.,Cobbold, S.A.,Bernardini, J.P.,Richardson, L.W.,Wang, X.S.,Lechtenberg, B.C.
Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216.
Mol.Cell, 82:598-615.e8, 2022

PubMed Abstract: An increasing number of genetic diseases are linked to deregulation of E3 ubiquitin ligases. Loss-of-function mutations in the RING-between-RING (RBR) family E3 ligase RNF216 (TRIAD3) cause Gordon-Holmes syndrome (GHS) and related neurodegenerative diseases. Functionally, RNF216 assembles K63-linked ubiquitin chains and has been implicated in regulation of innate immunity signaling pathways and synaptic plasticity. Here, we report crystal structures of key RNF216 reaction states including RNF216 in complex with ubiquitin and its reaction product, K63 di-ubiquitin. Our data provide a molecular explanation for chain-type specificity and reveal the molecular basis for disruption of RNF216 function by pathogenic GHS mutations. Furthermore, we demonstrate how RNF216 activity and chain-type specificity are regulated by phosphorylation and that RNF216 is allosterically activated by K63-linked di-ubiquitin. These molecular insights expand our understanding of RNF216 function and its role in disease and further define the mechanistic diversity of the RBR E3 ligase family.

PubMed: 34998453
DOI: 10.1016/j.molcel.2021.12.005

Experimental method

X-RAY DIFFRACTION (2.39 Å)