ERAD-associated E3 ubiquitin-protein ligase HRD1

UniProtKB accession:  Q08109

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UniProtKB description:  E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC1 and UBC7 E2 ligases, and transfers it to substrates promoting their degradation. Mediates the degradation of endoplasmic reticulum proteins (ERQC), also called ER-associated degradation (ERAD). Component of the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). In ERAD-L, facilitates retrotranslocation of misfolded proteins from the ER lumen through the ER membrane in conjunction with DER1 (PubMed:32327568). Both proteins have lateral gates facing each other which form a channel through the ER membrane and which distort the membrane region between the lateral gates, making it much thinner than a normal phospholipid bilayer (PubMed:32327568). Substrates insert into the membrane as a hairpin loop with one strand interacting with DER1 and the other with HRD1. ERAD-L substrates are ubiquitinated through HRD1 in conjunction with the E2 ubiquitin-conjugating enzymes UBC1 and UBC7-CUE1. Ubiquitinated substrates are then removed to the cytosol via the action of the CDC48-NPL4-UFD1 ATPase complex and targeted to the proteasome. ERAD-M substrates are processed by the same HRD1-HRD3 core complex, but only a subset of the other components is required for ERAD-M.