Misfolded proteins are recognized and cleared from the endoplasmic reticulum (ER) through ER-associated degradation (ERAD). This degradation depends on the ubiquitin–proteasome pathway and the recognition of substrates by adaptive ubiquitin E3 ligases. The E3 ligase Hrd1 works with numerous co-factors to form the core of the functional ERAD complex. Whereas interactions of Hrd1 with co-factors, such as the membrane-bound Herp and FAM8A1, are known, it is not well understood how these interactions come about to form the ERAD complex. In this issue (p. 3322), John Christianson and colleagues identify a specific cytoplasmic domain of Hrd1 that is evolutionarily conserved and required for the interaction with ERAD components. This domain, named HAF-H, lies in the intrinsically disordered part of Hrd1 and is needed for association of Hrd1 with FAM8A1 and Herp. Through the HAF-H domain, Hrd1 is able to form higher-order ERAD complexes for Hrd-1-dependent substrates and FAM8A1 enforces the native conformation of Hrd1 in the complex. This work highlights a new protein interaction domain in the E3 ligase Hrd1, which has a central role for the assembly and activity of the ERAD system that is required for ER homeostasis and the prevention of proteotoxic stress.
A new domain for an E3 ubiquitin ligase Free
A new domain for an E3 ubiquitin ligase. J Cell Sci 1 October 2017; 130 (19): e1905. doi:
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