Structures of the UBR4 complex reveal a giant arena to capture diverse substrates for ubiquitin chain elongation.
TL;DR
Recent cryo-EM structures of full-length UBR4 in complex with its cofactors KCMF1 and calmodulin, combined with crystal structures of key domains, reveal how UBR4 employs a giant arena lined with substrate-binding domains to capture defective proteins, as well as the mechanism of K48-specific ubiquitin chain extension.
Abstract
Ubiquitin ligases, members of the protein quality control machinery, target misassembled, and mislocalized proteins for degradation by tagging them with ubiquitin. The giant ubiquitin ligase UBR4 has emerged as a central regulator of protein fate by selecting a wide range of ubiquitinated protein substrates and extending degradative K48-linked chains on them-an activity which classifies it as an E4 ligase. Recent cryo-EM structures of full-length UBR4 in complex with its cofactors KCMF1 and calmodulin, combined with crystal structures of key domains, reveal how UBR4 employs a giant arena lined with substrate-binding domains to capture defective proteins, as well as the mechanism of K48-specific ubiquitin chain extension. Here, we review this structural and mechanistic data and discuss how it connects the diverse cellular functions of UBR4.