Crystal structure of SEL1L: Insight into the roles of SLR motifs in ERAD pathway

Abstract

Terminally misfolded proteins are selectively recognized and cleared by the endoplasmic reticulum-associated degradation (ERAD) pathway. SEL1L, a component of the ERAD machinery, plays an important role in selecting and transporting ERAD substrates for degradation. We have determined the crystal structure of the mouse SEL1L central domain comprising five Sel1-Like Repeats (SLR motifs 5 to 9; hereafter called SEL1Lcent). Strikingly, SEL1Lcent forms a homodimer with two-fold symmetry in a head-to-tail manner. Particularly, the SLR motif 9 plays an important role in dimer formation by adopting a domain-swapped structure and providing an extensive dimeric interface. We identified that the full-length SEL1L forms a self-oligomer through the SEL1Lcent domain in mammalian cells. Furthermore, we discovered that the SLR-C, comprising SLR motifs 10 and 11, of SEL1L directly interacts with the N-terminus luminal loops of HRD1. Therefore, we propose that certain SLR motifs of SEL1L play a unique role in membrane bound ERAD machinery.

The structure of Legionella effector protein LpnE provides insights into its interaction with Oculocerebrorenal syndrome of Lowe (OCRL) protein

“…SLR proteins are prevalent in nature and many structures of proteins containing these domains are known. Comparison of LpnE(73‐375) with other such proteins using the DALI server identified EsiB (PDB code http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4BWR ) from extra‐intestinal pathogenic E. coli (ExPEC), HcpB (PDB code http://www.rcsb.org/pdb/search/structidSearch.do?structureId=1KLX ), HcpC (PDB code http://www.rcsb.org/pdb/search/structidSearch.do?structureId=1OUV ) of the Helicobacter pylori cysteine‐rich (Hcp) family and mouse SEL1L (PDB code http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5B26 ) of the ER‐associated protein degradation (ERAD) machinery as the closest structural homologs. EsiB, HcpB, and HcpC are all SLR proteins from bacterial pathogens and their roles in virulence remain uncertain.…”

New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation

“…In addition to transcriptional induction by extracellular signals that are detailed below, two most prominent regulatory mechanisms for Hrd1 ERAD activity are Hrd1 self-ubiquitination (see above) and its interaction with the cofactor Sel1L (38, 39). Sel1L, a type I transmembrane protein with a large luminal domain (45), may form a dimer or oligomer and interact with the N-terminal domain of Hrd1 (46). Sel1L is necessary for the ERAD process for a subset of model substrates (29, 37-40) as well as endogenous substrates including luminal hedgehog (47), transmembrane CD147 (48) and ATF6 (49).…”

Functional Innovation in the Evolution of the Calcium-Dependent System of the Eukaryotic Endoplasmic Reticulum

“…The SLRs of wolframin appear most closely-related to bacterial versions, suggesting a possible horizontal transfer at the base of animals (Ponting et al, 1999); however, the short length and rapid divergence of such repeats complicates definitive ascertainment of such evolutionary relationships. SLRs and related a/a repeats are often involved in coordinating interactions within protein complexes (Karpenahalli et al, 2007;Mittl and Schneider-Brachert, 2007) and have been characterized specifically in ER stress and misfolded protein degradation responses (Jeong et al, 2016) and in mediating interactions of membrane-associated protein complexes (Mittl and Schneider-Brachert, 2007). As the wolframin SLRs roughly correspond to an experimentallydetermined calmodulin-binding region (Yurimoto et al, 2009), they might specifically mediate that protein interaction.…”