| Structural highlights
Disease
S61A1_HUMAN The disease is caused by variants affecting the gene represented in this entry. Defects in SEC61A1 may be a cause of autosomal dominant hypogammaglobulinemia, resulting in severe recurrent infections, mainly of the respiratory tract. Disease onset is mostly in the first year of life. Affected subjects manifest reduced antibodies production by plasma cells, in the presence of normal subpopulations of B and T cells in the peripheral blood. Patients respond well to immunoglobulin replacement therapy.[1]
Function
S61A1_HUMAN Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939, PubMed:22375059, PubMed:28782633, PubMed:29719251, PubMed:32814900). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (PubMed:22375059, PubMed:28782633, PubMed:29719251). May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins (PubMed:22375059, PubMed:29719251). The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:8616892). Controls the passive efflux of calcium ions from the ER lumen to the cytosol through SEC61 channel, contributing to the maintenance of cellular calcium homeostasis (PubMed:28782633). Plays a critical role in nephrogenesis, specifically at pronephros stage (By similarity).[UniProtKB:P61620][2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design.
A common mechanism of Sec61 translocon inhibition by small molecules.,Itskanov S, Wang L, Junne T, Sherriff R, Xiao L, Blanchard N, Shi WQ, Forsyth C, Hoepfner D, Spiess M, Park E Nat Chem Biol. 2023 May 11. doi: 10.1038/s41589-023-01337-y. PMID:37169959[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M, Bulashevska A, Kemming J, Kühn J, Winzer S, Rusch S, Fliegauf M, Schäffer AA, Pfeffer S, Geiger R, Cavalié A, Cao H, Yang F, Li Y, Rizzi M, Eibel H, Kobbe R, Marks AL, Peppers BP, Hostoffer RW, Puck JM, Zimmermann R, Grimbacher B. Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J Allergy Clin Immunol. 2018 Apr;141(4):1427-1438. PMID:28782633 doi:10.1016/j.jaci.2017.06.042
- ↑ Meacock SL, Lecomte FJ, Crawshaw SG, High S. Different transmembrane domains associate with distinct endoplasmic reticulum components during membrane integration of a polytopic protein. Mol Biol Cell. 2002 Dec;13(12):4114-29. PMID:12475939 doi:10.1091/mbc.e02-04-0198
- ↑ Lang S, Benedix J, Fedeles SV, Schorr S, Schirra C, Schauble N, Jalal C, Greiner M, Hassdenteufel S, Tatzelt J, Kreutzer B, Edelmann L, Krause E, Rettig J, Somlo S, Zimmermann R, Dudek J. Different effects of Sec61alpha, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells. J Cell Sci. 2012 Apr 15;125(Pt 8):1958-69. doi: 10.1242/jcs.096727. Epub 2012 Feb, 28. PMID:22375059 doi:http://dx.doi.org/10.1242/jcs.096727
- ↑ Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M, Bulashevska A, Kemming J, Kühn J, Winzer S, Rusch S, Fliegauf M, Schäffer AA, Pfeffer S, Geiger R, Cavalié A, Cao H, Yang F, Li Y, Rizzi M, Eibel H, Kobbe R, Marks AL, Peppers BP, Hostoffer RW, Puck JM, Zimmermann R, Grimbacher B. Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J Allergy Clin Immunol. 2018 Apr;141(4):1427-1438. PMID:28782633 doi:10.1016/j.jaci.2017.06.042
- ↑ Hassdenteufel S, Johnson N, Paton AW, Paton JC, High S, Zimmermann R. Chaperone-Mediated Sec61 Channel Gating during ER Import of Small Precursor Proteins Overcomes Sec61 Inhibitor-Reinforced Energy Barrier. Cell Rep. 2018 May 1;23(5):1373-1386. doi: 10.1016/j.celrep.2018.03.122. PMID:29719251 doi:http://dx.doi.org/10.1016/j.celrep.2018.03.122
- ↑ Chitwood PJ, Hegde RS. An intramembrane chaperone complex facilitates membrane protein biogenesis. Nature. 2020 Aug;584(7822):630-634. PMID:32814900 doi:10.1038/s41586-020-2624-y
- ↑ McGilvray PT, Anghel SA, Sundaram A, Zhong F, Trnka MJ, Fuller JR, Hu H, Burlingame AL, Keenan RJ. An ER translocon for multi-pass membrane protein biogenesis. Elife. 2020 Aug 21;9:e56889. PMID:32820719 doi:10.7554/eLife.56889
- ↑ Sundaram A, Yamsek M, Zhong F, Hooda Y, Hegde RS, Keenan RJ. Substrate-driven assembly of a translocon for multipass membrane proteins. Nature. 2022 Nov;611(7934):167-172. PMID:36261522 doi:10.1038/s41586-022-05330-8
- ↑ Do H, Falcone D, Lin J, Andrews DW, Johnson AE. The cotranslational integration of membrane proteins into the phospholipid bilayer is a multistep process. Cell. 1996 May 3;85(3):369-78. PMID:8616892 doi:10.1016/s0092-8674(00)81115-0
- ↑ Itskanov S, Wang L, Junne T, Sherriff R, Xiao L, Blanchard N, Shi WQ, Forsyth C, Hoepfner D, Spiess M, Park E. A common mechanism of Sec61 translocon inhibition by small molecules. Nat Chem Biol. 2023 May 11. PMID:37169959 doi:10.1038/s41589-023-01337-y
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