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-Structure paper
タイトル | Structural insights into TRAP association with ribosome-Sec61 complex and translocon inhibition by a CADA derivative. |
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ジャーナル・号・ページ | Sci Adv, Vol. 9, Issue 9, Page eadf0797, Year 2023 |
掲載日 | 2023年3月3日 |
著者 | Eva Pauwels / Neesha R Shewakramani / Brent De Wijngaert / Anita Camps / Becky Provinciael / Joren Stroobants / Kai-Uwe Kalies / Enno Hartmann / Piet Maes / Kurt Vermeire / Kalyan Das / |
PubMed 要旨 | During cotranslational translocation, the signal peptide of a nascent chain binds Sec61 translocon to initiate protein transport through the endoplasmic reticulum (ER) membrane. Our cryo-electron ...During cotranslational translocation, the signal peptide of a nascent chain binds Sec61 translocon to initiate protein transport through the endoplasmic reticulum (ER) membrane. Our cryo-electron microscopy structure of ribosome-Sec61 shows binding of an ordered heterotetrameric translocon-associated protein (TRAP) complex, in which TRAP-γ is anchored at two adjacent positions of 28 ribosomal RNA and interacts with ribosomal protein L38 and Sec61α/γ. Four transmembrane helices (TMHs) of TRAP-γ cluster with one C-terminal helix of each α, β, and δ subunits. The seven TMH bundle helps position a crescent-shaped trimeric TRAP-α/β/δ core in the ER lumen, facing the Sec61 channel. Further, our in vitro assay establishes the cyclotriazadisulfonamide derivative CK147 as a translocon inhibitor. A structure of ribosome-Sec61-CK147 reveals CK147 binding the channel and interacting with the plug helix from the lumenal side. The CK147 resistance mutations surround the inhibitor. These structures help in understanding the TRAP functions and provide a new Sec61 site for designing translocon inhibitors. |
リンク | Sci Adv / PubMed:36867692 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.79 - 2.86 Å |
構造データ | EMDB-15860, PDB-8b5l: EMDB-15863, PDB-8b6c: |
化合物 | ChemComp-MG: ChemComp-ZN: ChemComp-OWI: |
由来 |
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キーワード | MEMBRANE PROTEIN / Ribosome / Sec61 / TRAP / Translocon / Translation / RNA binding protein / eEF2 / CK147 / CADA / Translocon inhibitor / 80S / 60S / 40S / cyclotriazadisulfonamide |