Membrane Protein Biogenesis: PAT Complex Pats Membrane Proteins into Shape

Culver, Jacob A.; Mariappan, Malaiyalam

doi:10.1016/j.cub.2020.09.072

Cited by 2 publications

(3 citation statements)

References 18 publications

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“…(A) Schematics of the TMCO1 translocon and the topologies and domain structures of each subunit [117]: TMEM147 is the core subunit of the Nicalin‐TMEM147‐NOMO complex [119] which, when assembled into the Sec61‐TMCO1‐RNC complex (NOMO not depicted), lines a lipid cavity at the centre of this transient complex. (B) The CCDC47 and Asterix subunits of the PAT complex form a stable heterodimer [122], but its precise relationship to the TMCO1 translocon, if any, is unclear [126]. Based on its proximity to the ribosomal exit tunnel [117], CCDC47 may be able to sense hydrophilic TMD residues and recruit Asterix into the wider TMCO1 complex.…”

Section: New Routes For Insertion and Folding: Tmco1 And The Pat Complexmentioning

confidence: 99%

“…In the case of TMDs that are inserted via the Sec61‐containing TMCO1 translocon, one possibility is that hydrophilic TMDs may be sequentially handed over to the PAT complex until the assembly of a multi‐span TMP is complete (Fig. 5C) [126]. In this scenario, the interaction of CCDC47 with the Sec61‐bound ribosome near its exit tunnel could provide an important physical link that enables client TMDs to access the substrate‐binding Asterix subunit of the PAT complex.…”

Section: New Routes For Insertion and Folding: Tmco1 And The Pat Complexmentioning

confidence: 99%

“…In this scenario, the interaction of CCDC47 with the Sec61‐bound ribosome near its exit tunnel could provide an important physical link that enables client TMDs to access the substrate‐binding Asterix subunit of the PAT complex. However, it should be noted that at present there is no direct evidence that TMCO1‐associated CCDC47 is also in complex with Asterix [117,126].…”

Section: New Routes For Insertion and Folding: Tmco1 And The Pat Complexmentioning

confidence: 99%

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Membrane protein biogenesis at the ER: the highways and byways

2021

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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.

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