Membrane protein biogenesis at the ER: the highways and byways

Abstract

The Sec61 complex is the major protein translocation channel of the endoplasmic reticulum (ER), where it plays a central role in the biogenesis of membrane and secretory proteins. Whilst Sec61-mediated protein translocation is typically coupled to polypeptide synthesis, suggestive of significant complexity, an obvious characteristic of this core translocation machinery is its surprising simplicity. Over thirty years after its initial discovery, we now understand that the Sec61 complex is in fact the central piece of an elaborate jigsaw puzzle, which can be partly solved using new research findings. We propose that the Sec61 complex acts as a dynamic hub for cotranslational protein translocation at the ER, proactively recruiting a range of accessory complexes that enhance and regulate its function in response to different protein clients. It is now clear that the Sec61 complex does not have a monopoly on co-translational insertion, with some transmembrane proteins preferentially utilising the ER membrane complex instead. We also have a better understanding of post-insertion events, where at least one membrane-embedded chaperone complex can capture the newly inserted transmembrane domains of multi-span proteins and co-ordinate their assembly into a native structure. Having discovered this array of Sec61-associated components and competitors, our next challenge is to understand how they act together in order to expand the range and complexity of the membrane proteins that can be synthesised at the ER. Furthermore, this diversity of components and pathways may open up new opportunities for targeted therapeutic interventions designed to selectively modulate protein biogenesis at the ER. AbbreviationsBiP, immunoglobulin binding protein; CCDC47, coiled-coil domain containing 47 protein, also known as calumin; EMC, ER membrane complex; ER, endoplasmic reticulum; GET, guided entry of tail-anchored proteins; hSnd2, human SRP-independent protein 2, also known as TMEM208; NAC, nascent polypeptide-associated complex; NOMO, nodal modulating protein; PAT, protein associated with the ER translocon; RNC, ribosome-nascent chain; SGTA, small glutamine-rich tetratricopeptide repeat-containing protein alpha; SND, SRPindependent proteins or pathway; SPC, signal peptidase complex; SRP, signal recognition particle; TA, tail-anchored; TMCO1, transmembrane and coiled-coil domains 1 protein; TMD, transmembrane domain; TMEM147, transmembrane protein 147; TMEM208, transmembrane protein 208; TMP, transmembrane protein; TRAM, translocating chain-associated membrane protein; TRAP, transloconassociated protein; TRC40, transmembrane recognition complex of 40 kDa, also known as Asna1.

Lights, Camera, Interaction: Studying Protein–Protein Interactions of the ER Protein Translocase in Living Cells

“…Once substrates with special requirements start the gating process, Sec61β allows rapid integration of Sec63 into the active translocon. If so, Sec61β and Sec63 eventually will show a partially overlapping substrate-spectrum, which remains to be seen [6,18,67]. This scenario is reminiscent of a previous report showing the recruitment of the signal peptidase complex to the active, ribosome-engaged translocon by Sec61β [68].…”

Co-translational biogenesis of lipid droplet integral membrane proteins

“…The majority of integral membrane proteins destined for the secretory pathway are co-translationally targeted to, and inserted into, the ER membrane via a pathway that is initiated by the signal recognition particle (SRP) ( O'Keefe et al, 2021a ). Hence, the SRP binds to a hydrophobic N-terminal signal sequence or the first transmembrane domain (TMD) of a nascent membrane protein as soon as it emerges from the ribosome, and targets the ribosome-nascent chain complex to the ER where the SRP interacts with its membrane-tethered receptor SR (a heterodimer of SRPRA, which is referred to here as SRα, and SRPRB).…”

Take Me Home, Protein Roads: Structural Insights into Signal Peptide Interactions during ER Translocation

“…The ER translocon is a dynamic super-complex at the ER membrane that facilitates the translocation, folding, and post-translational modification of many NCs ( Figure 4 ). In addition to its central component Sec61, the ER translocon features a portfolio of sub-complexes with specific auxiliary functions that can be proactively recruited in a sub-stoichiometric manner depending on the type of SS at hand [ 11 , 80 ]. Some, such as the translocon-associated protein complex (TRAP), are associated near-stoichiometrically to the co-translational ER translocon ( Figure 4 ), while others such as the SPC can act in concert but are not or only transiently recruited [ 81 ].…”

“…In this review, we delineate the lessons learned from the structural characterization of the different secretory machineries and their interactions with SPs, starting at the ribosomal exit tunnel and ending in the ER membrane. For the targeting and translocation of non-SP SSs, we refer to several excellent recent reviews [ 9 , 10 , 11 ].…”