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TitleA molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateAug 1, 2025
AuthorsEmir Maldosevic / Radoslaw Gora / Liangguang Leo Lin / Linyao Elina Zhou / Zexin Jason Li / Yelena Peskova / Ling Qi / Shu-Ou Shan / Ahmad Jomaa
PubMed AbstractThe nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to the signal recognition particle (SRP) to ensure the fidelity of protein ...The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to the signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identified a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increases NAC barrel dynamics and reduces its binding to the ribosome. This leads to an impaired ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing novel insights into protein targeting fidelity with broader implications for cellular proteostasis.
External linksbioRxiv / PubMed:40766658 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 3.04 Å
Structure data

48552

9mr4

EMDB-48552, PDB-9mr4:
NAC: Ribosome nascent chain complex(Oxa1L)
Method: EM (single particle) / Resolution: 2.65 Å

EMDB-71310: NAC: ribosome nascent chain complex (Hsp60)
Method: EM (single particle) / Resolution: 3.04 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsRIBOSOME / NAC / mitochondrial sorting

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