Jeong Hanbin, Sim Hyo Jung, Song Eun Kyung, Lee Hakbong, Ha Sung Chul, Jun Youngsoo, Park Tae Joo, Lee Changwook
Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST-gil, Ulsan 44919, Republic of Korea.
Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang, Kyungbuk 37673, Korea.
Sci Rep. 2016 Feb 9;6:20261. doi: 10.1038/srep20261.
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 SEL1L(cent)). Strikingly, SEL1L(cent) 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 SEL1L(cent) 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.
终末错误折叠的蛋白质通过内质网相关降解（ERAD）途径被选择性识别并清除。SEL1L是ERAD机制的一个组成部分，在选择和转运ERAD底物进行降解方面发挥着重要作用。我们已经确定了小鼠SEL1L中央结构域的晶体结构，该结构域由五个Sel1样重复序列（SLR基序5至9；以下称为SEL1L(cent)）组成。引人注目的是，SEL1L(cent)以头对尾的方式形成具有二重对称性的同二聚体。特别地，SLR基序9通过采用结构域交换结构并提供广泛的二聚体界面，在二聚体形成中发挥重要作用。我们发现全长SEL1L在哺乳动物细胞中通过SEL1L(cent)结构域形成自寡聚体。此外，我们发现SEL1L的SLR-C（由SLR基序10和11组成）直接与HRD1的N端腔内环相互作用。因此，我们提出SEL1L的某些SLR基序在膜结合的ERAD机制中发挥独特作用。
