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The mechanisms of integral membrane protein biogenesis

Nature Reviews Molecular Cell Biology volume 23, pages 107–124 (2022)Cite this article

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Abstract

Roughly one quarter of all genes code for integral membrane proteins that are inserted into the plasma membrane of prokaryotes or the endoplasmic reticulum membrane of eukaryotes. Multiple pathways are used for the targeting and insertion of membrane proteins on the basis of their topological and biophysical characteristics. Multipass membrane proteins span the membrane multiple times and face the additional challenges of intramembrane folding. In many cases, integral membrane proteins require assembly with other proteins to form multi-subunit membrane protein complexes. Recent biochemical and structural analyses have provided considerable clarity regarding the molecular basis of membrane protein targeting and insertion, with tantalizing new insights into the poorly understood processes of multipass membrane protein biogenesis and multi-subunit protein complex assembly.

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Fig. 1: Overview of integral membrane protein biogenesis.
Fig. 2: Membrane protein targeting to the endoplasmic reticulum.
Fig. 3: Membrane protein insertion at the endoplasmic reticulum.
Fig. 4: Structure and function of the Oxa1 superfamily insertases.
Fig. 5: Biogenesis of multipass membrane proteins.

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Acknowledgements

The authors thank members of the Hegde and Keenan laboratories for productive discussions that influenced this Review. R.S.H. is funded by the UK Medical Research Council (MC_UP_A022_1007). R.J.K. is funded by grants from the US National Institutes of Health (R01 GM086487 and R01 GM130051).

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  1. Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, UK

    Ramanujan S. Hegde

  2. Gordon Center for Integrative Science, The University of Chicago, Chicago, IL, USA

    Robert J. Keenan

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Glossary

Targeting sequence

The sequence element in a protein that directs its delivery to a specific membrane in the cell. For membrane proteins, the targeting sequence is typically a cleavable amino-terminal signal peptide or the first transmembrane domain.

Signal peptide

A targeting sequence that is found at the amino terminus of secretory proteins and some membrane proteins. After they have served their targeting function, signal peptides are cleaved off by an enzyme called ‘signal peptidase’.

Tail-anchored (TA) membrane proteins

Membrane proteins whose only transmembrane domain lies within ~65 amino acids of the carboxy terminus and are oriented with the amino terminus facing the cytosol. These are sometimes called ‘type IV membrane proteins’.

Sec61 complex

A heterotrimeric protein complex that translocates hydrophilic polypeptide segments across the membrane through an aqueous channel and inserts hydrophobic domains into the membrane through a lateral gate. It is called the ‘SecY complex’ in prokaryotes.

Insertases

Transmembrane proteins containing a hydrophilic vestibule that facilitates translocation of short polypeptide segments across the membrane concomitant with transmembrane domain insertion.

Oxa1 superfamily

An evolutionarily related group of membrane protein insertases that includes Oxa1 in the inner mitochondrial membrane, YidC in the bacterial inner membrane, Ylp1 in the archaeal plasma membrane, Alb3 in the chloroplast inner membrane, and GET1, EMC3 and TMCO1 in the eukaryotic endoplasmic reticulum.

Type I membrane proteins

Signal peptide-containing membrane proteins oriented with their mature amino terminus facing the lumen (a topology that is also termed ‘Nexo’) following signal peptide cleavage.

Type II membrane proteins

Membrane proteins oriented with their amino terminus facing the cytosol (a topology that is also termed ‘Ncyt’).

Type III membrane proteins

Membrane proteins oriented with their amino terminus facing the lumen (a topology that is also termed ‘Nexo’); these proteins typically possess a short (fewer than 50 amino acids) amino-terminal flanking region.

Multipass membrane proteins

Proteins spanning the membrane more than once.

Single-pass membrane proteins

Proteins spanning the membrane once.

Intramembrane chaperone

A factor that promotes folding in the membrane by temporarily shielding partially hydrophilic transmembrane domains of nascent polypeptides until their successful assembly with other transmembrane domains.

Chaperonin

A family of ATP-driven multimeric chaperone complexes characterized by a cylindrical structure with an internal chamber. The interior of the chaperonin cylinder provides a protected environment within which nascent proteins can fold.

Assembly factor

A factor that promotes the assembly of two or more proteins, possibly by temporarily shielding their inter-subunit interfaces.

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Hegde, R.S., Keenan, R.J. The mechanisms of integral membrane protein biogenesis. Nat Rev Mol Cell Biol 23, 107–124 (2022). https://doi.org/10.1038/s41580-021-00413-2

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