An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.

Autor:	Ji J; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Cui MK; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Zou R; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Wu MZ; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Ge MX; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Li J; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China., Zhang ZR; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100101, China. Electronic address: zrzhang@sioc.ac.cn.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 May 16; Vol. 84 (10), pp. 1917-1931.e15. Date of Electronic Publication: 2024 May 08.
DOI:	10.1016/j.molcel.2024.04.010
Abstrakt:	Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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