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.