title: Novel functions of ubiquitin ligase HRD1 with transmembrane and proline-rich domains.
abstract: Human ubiquitin ligase HRD1 is involved in endoplasmic reticulum-associated degradation (ERAD). We recently reported that HRD1 interacts with Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, and promotes Pael-R degradation, resulting in the protection of cells from the lethal accumulation of Pael-R. However, except for RING-finger domain that is necessary for ubiquitin ligase activity, the roles of other human HRD1 domains are unclear. Here, we show that the proline-rich domain of HRD1 is necessary to promote the degradation of Pael-R and that the protein's transmembrane domain is necessary to transfer Pael-R from the endoplasmic reticulum (ER) to the cytosol. A HRD1 mutant defective in the transmembrane domain is markedly more unstable than wild-type HRD1. These results suggest that HRD1 has diverse functions besides ubiquitin ligase activity.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.forename: Masayuki
authors.initials: M
authors.lastname: Onoguchi
authors.forename: Shinobu
authors.initials: S
authors.lastname: Koizumi
authors.forename: Miho
authors.initials: M
authors.lastname: Itami
authors.forename: Mariko
authors.initials: M
authors.lastname: Ueyama
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Okuma
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nomura
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
chemical_list: C480827:GPR37 receptor, human; D043562:Receptors, G-Protein-Coupled; D025801:Ubiquitin; D011392:Proline; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases