000			02152 am a22002413u 4500
042			_adc
100	1	0	_aSmalinskaitė, Luka _eauthor _92506
700	1	0	_aKim, Min Kyung _eauthor _92507
700	1	0	_aLewis, Aaron J. O. _eauthor _92508
700	1	0	_aKeenan, Robert J. _eauthor _92509
700	1	0	_aHegde, Ramanujan S. _eauthor _92510
245	0	0	_aMechanism of an intramembrane chaperone for multipass membrane proteins
260			_c2022-11-01.
500			_a/pmc/articles/PMC7614104/
500			_a/pubmed/36261528
520			_aMultipass membrane proteins play numerous roles in biology and include receptors, transporters, ion channels, and enzymes(1,2). How multipass proteins are co-translationally inserted and folded at the endoplasmic reticulum (ER) is not well understood(2). The prevailing model posits that each transmembrane domain (TMD) of a multipass protein successively passes into the lipid bilayer through a front-side lateral gate of the Sec61 protein translocation channel(3-9). The PAT complex, an intramembrane chaperone comprising Asterix and CCDC47, engages early TMDs of multipass proteins to promote their biogenesis by an unknown mechanism(10). Here, biochemical and structural analysis of intermediates during multipass protein biogenesis revealed that the nascent chain is not engaged with Sec61, which is occluded and latched closed by CCDC47. Instead, Asterix binds to and redirects the substrate behind Sec61, where the PAT complex contributes to a multipass translocon surrounding a semi-enclosed lipid-filled cavity(11). Detection of multiple TMDs in this cavity after their emergence from the ribosome suggests that multipass proteins insert and fold behind Sec61. Accordingly, biogenesis of several multipass proteins was unimpeded by inhibitors of the Sec61 lateral gate. These findings elucidate the mechanism of an intramembrane chaperone and suggest a new framework for multipass membrane protein biogenesis at the ER.
540			_a
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nNature
856	4	1	_uhttp://dx.doi.org/10.1038/s41586-022-05336-2 _zConnect to this object online.
999			_c927 _d927