Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD)
| Autor: | John C. Christianson, Lena-Sophie Dreher, Jasmin Schulz, Emma J. Fenech, Dönem Avci, Thorsten Hoppe, Yuki Hayashi, Norbert Volkmar, Markus A. Queisser, Aljona Gutschmidt |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
HRD1 ubiquitin ligase complex Ubiquitin-Protein Ligases Complex formation macromolecular substances Endoplasmic-reticulum-associated protein degradation Bioinformatics Models Biological Cofactor 03 medical and health sciences 0302 clinical medicine Humans Er associated degradation biology Membrane Proteins Endoplasmic Reticulum-Associated Degradation Cell Biology Ubiquitin ligase Cell biology HEK293 Cells 030104 developmental biology Cytoplasm biology.protein Protein folding 030217 neurology & neurosurgery Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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