Open AccessConserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD)
Author(s) -
Jasmin Schulz,
Dönem Avci,
Markus A. Queisser,
Aljona Gutschmidt,
LenaSophie Dreher,
Emma J Fenech,
Norbert Volkmar,
Yoshihiko Hayashi,
Thorsten Hoppe,
John C. Christianson
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.206847
Subject(s) - endoplasmic reticulum associated protein degradation , ubiquitin ligase , biology , ubiquitin , cytoplasm , microbiology and biotechnology , proteasome , ubiquitin protein ligases , domain (mathematical analysis) , biochemistry , gene , mathematical analysis , mathematics
The mammalian ubiquitin ligase Hrd1 is the central component of a complex facilitating degradation of misfolded proteins during the ubiquitin-proteasome-dependent process of ER-associated degradation (ERAD). Hrd1 associates with cofactors to execute ERAD, but their roles and how they assemble with Hrd1 are not well understood. Here, we identify crucial cofactor interaction domains within Hrd1 and report a previously unrecognised evolutionarily conserved segment within the intrinsically disordered cytoplasmic domain of Hrd1 (termed the HAF-H domain), which engages complementary segments in the cofactors FAM8A1 and Herp (also known as HERPUD1). This domain is required by Hrd1 to interact with both FAM8A1 and Herp, as well as to assemble higher-order Hrd1 complexes. FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery.