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Watching helical membrane proteins fold reveals a common N-to-C-terminal folding pathway

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Science  29 Nov 2019:
Vol. 366, Issue 6469, pp. 1150-1156
DOI: 10.1126/science.aaw8208

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A pathway for helical membrane proteins

Membrane proteins are inserted into cell membranes while they are being translated and may fold concurrently into their secondary and tertiary structures. Choi et al. describe a single-molecule force microscopy technique that allowed them to monitor folding of helical membrane proteins in vesicles and bicelles. Two helical membrane proteins, the Escherichia coli rhomboid protease GlpG and the human β2-adrenergic receptor, both folded from the N to the C terminus, with structures forming in units of helical hairpins. In the cell, this would allow these proteins to begin folding while being translated.

Science, this issue p. 1150

Abstract

To understand membrane protein biogenesis, we need to explore folding within a bilayer context. Here, we describe a single-molecule force microscopy technique that monitors the folding of helical membrane proteins in vesicle and bicelle environments. After completely unfolding the protein at high force, we lower the force to initiate folding while transmembrane helices are aligned in a zigzag manner within the bilayer, thereby imposing minimal constraints on folding. We used the approach to characterize the folding pathways of the Escherichia coli rhomboid protease GlpG and the human β2-adrenergic receptor. Despite their evolutionary distance, both proteins fold in a strict N-to-C-terminal fashion, accruing structures in units of helical hairpins. These common features suggest that integral helical membrane proteins have evolved to maximize their fitness with cotranslational folding.

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