Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon

Overview

Journal J Mol Recognit

Specialty Molecular Biology

Date 2024 Oct 12

PMID 39394908

Authors

Nidhi Sorout

Volkhard Helms

Affiliations

Soon will be listed here.

Abstract

The Sec61 translocon mediates the translocation of numerous, newly synthesized precursor proteins into the lumen of the endoplasmic reticulum or their integration into its membrane. Recently, structural biology revealed conformations of idle or substrate-engaged Sec61, and likewise its interactions with the accessory membrane proteins Sec62, Sec63, and TRAP, respectively. Several natural and synthetic small molecules have been shown to block Sec61-mediated protein translocation. Since this is a key step in protein biogenesis, broad inhibition is generally cytotoxic, which may be problematic for a putative drug target. Interestingly, several compounds exhibit client-selective modes of action, such that only translocation of certain precursor proteins was affected. Here, we discuss recent advances of structural biology, molecular modelling, and molecular screening that aim to use Sec61 as feasible drug target.

References

Junne T, Wong J, Studer C, Aust T, Bauer B, Beibel M . Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon. J Cell Sci. 2015; 128(6):1217-29. PMC: 4359925. DOI: 10.1242/jcs.165746. View

Pauwels E, Rutz C, Provinciael B, Stroobants J, Schols D, Hartmann E . A Proteomic Study on the Membrane Protein Fraction of T Cells Confirms High Substrate Selectivity for the ER Translocation Inhibitor Cyclotriazadisulfonamide. Mol Cell Proteomics. 2021; 20:100144. PMC: 8477212. DOI: 10.1016/j.mcpro.2021.100144. View

Chitwood P, Hegde R . An intramembrane chaperone complex facilitates membrane protein biogenesis. Nature. 2020; 584(7822):630-634. PMC: 7610463. DOI: 10.1038/s41586-020-2624-y. View

Santos L, Ferreira R, Caffarena E . Integrating Molecular Docking and Molecular Dynamics Simulations. Methods Mol Biol. 2019; 2053:13-34. DOI: 10.1007/978-1-4939-9752-7_2. View

Deshaies R, Sanders S, Feldheim D, Schekman R . Assembly of yeast Sec proteins involved in translocation into the endoplasmic reticulum into a membrane-bound multisubunit complex. Nature. 1991; 349(6312):806-8. DOI: 10.1038/349806a0. View

Cannon K, Or E, Clemons Jr W, Shibata Y, Rapoport T . Disulfide bridge formation between SecY and a translocating polypeptide localizes the translocation pore to the center of SecY. J Cell Biol. 2005; 169(2):219-25. PMC: 2171872. DOI: 10.1083/jcb.200412019. View

Shah P, Link N, Jang G, Sharp P, Zhu T, Swaney D . Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis. Cell. 2018; 175(7):1931-1945.e18. PMC: 6474419. DOI: 10.1016/j.cell.2018.11.028. View

Clemons Jr W, Menetret J, Akey C, Rapoport T . Structural insight into the protein translocation channel. Curr Opin Struct Biol. 2004; 14(4):390-6. DOI: 10.1016/j.sbi.2004.07.006. View

Gumbart J, Schulten K . Molecular dynamics studies of the archaeal translocon. Biophys J. 2006; 90(7):2356-67. PMC: 1403164. DOI: 10.1529/biophysj.105.075291. View

10.

Wang J, Youkharibache P, Zhang D, Lanczycki C, Geer R, Madej T . iCn3D, a web-based 3D viewer for sharing 1D/2D/3D representations of biomolecular structures. Bioinformatics. 2019; 36(1):131-135. PMC: 6956771. DOI: 10.1093/bioinformatics/btz502. View

11.

Gumbart J, Trabuco L, Schreiner E, Villa E, Schulten K . Regulation of the protein-conducting channel by a bound ribosome. Structure. 2009; 17(11):1453-64. PMC: 2778611. DOI: 10.1016/j.str.2009.09.010. View

12.

Chen Q, Liu Y, Luesch H . Systematic Chemical Mutagenesis Identifies a Potent Novel Apratoxin A/E Hybrid with Improved in Vivo Antitumor Activity. ACS Med Chem Lett. 2011; 2(11):861-865. PMC: 3212850. DOI: 10.1021/ml200176m. View

13.

Mackinnon A, Garrison J, Hegde R, Taunton J . Photo-leucine incorporation reveals the target of a cyclodepsipeptide inhibitor of cotranslational translocation. J Am Chem Soc. 2007; 129(47):14560-1. PMC: 2574519. DOI: 10.1021/ja076250y. View

14.

Gamayun I, OKeefe S, Pick T, Klein M, Nguyen D, McKibbin C . Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca Leakage from the Endoplasmic Reticulum. Cell Chem Biol. 2019; 26(4):571-583.e6. PMC: 6483976. DOI: 10.1016/j.chembiol.2019.01.010. View

15.

Halic M, Becker T, Pool M, Spahn C, Grassucci R, Frank J . Structure of the signal recognition particle interacting with the elongation-arrested ribosome. Nature. 2004; 427(6977):808-14. DOI: 10.1038/nature02342. View

16.

Gemmer M, Chaillet M, van Loenhout J, Cuevas Arenas R, Vismpas D, Grollers-Mulderij M . Visualization of translation and protein biogenesis at the ER membrane. Nature. 2023; 614(7946):160-167. PMC: 9892003. DOI: 10.1038/s41586-022-05638-5. View

17.

Domenger A, Choisy C, Baron L, Mayau V, Perthame E, Deriano L . The Sec61 translocon is a therapeutic vulnerability in multiple myeloma. EMBO Mol Med. 2022; 14(3):e14740. PMC: 8899908. DOI: 10.15252/emmm.202114740. View

18.

Van Puyenbroeck V, Claeys E, Schols D, Bell T, Vermeire K . A Proteomic Survey Indicates Sortilin as a Secondary Substrate of the ER Translocation Inhibitor Cyclotriazadisulfonamide (CADA). Mol Cell Proteomics. 2016; 16(2):157-167. PMC: 5294205. DOI: 10.1074/mcp.M116.061051. View

19.

Goder V, Junne T, Spiess M . Sec61p contributes to signal sequence orientation according to the positive-inside rule. Mol Biol Cell. 2003; 15(3):1470-8. PMC: 363169. DOI: 10.1091/mbc.e03-08-0599. View

20.

Vermeire K, Zhang Y, Princen K, Hatse S, Samala M, Dey K . CADA inhibits human immunodeficiency virus and human herpesvirus 7 replication by down-modulation of the cellular CD4 receptor. Virology. 2002; 302(2):342-53. DOI: 10.1006/viro.2002.1624. View