Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex
Secretory proteins are critically dependent on the correct processing of their signal sequence by the signal peptidase complex (SPC). This step, which is essential for the proper folding and localization of proteins in eukaryotic cells, is still not fully understood. In eukaryotes, the SPC comprises four evolutionarily conserved membrane subunits (Spc1-3 and Sec11). Here, we investigated the role of Spc2, examining SPC cleavage efficiency on various models and natural signal sequences in yeast cells depleted of or with mutations in Spc2. Our data show that discrimination between substrates and identification of the cleavage site by SPC is compromised when Spc2 is absent or mutated. Molecular dynamics simulation of the yeast SPC AlphaFold2-Multimer model indicates that membrane thinning at the center of SPC is reduced without Spc2, suggesting a molecular explanation for the altered substrate recognition properties of SPC lacking Spc2. These results provide new insights into the molecular mechanisms by which SPC governs protein biogenesis.
Authors
- Yeonji Chung
- Gunnar von Heijne (ORCID: https://orcid.org/0000-0002-4490-8569)
- Chewon Yim (ORCID: https://orcid.org/0000-0002-0200-8458)
- Paulo C. T. Souza (ORCID: https://orcid.org/0000-0003-0660-1301)
- Gilberto P. Pereira (ORCID: https://orcid.org/0000-0002-6277-0006)
- Amy M. Weeks (ORCID: https://orcid.org/0000-0003-4700-8256)
- Friedrich Förster (ORCID: https://orcid.org/0000-0002-6044-2746)
- Lisbeth R. Kjølbye (ORCID: https://orcid.org/0000-0003-2834-3411)
- Hyun Kim
- Sungjoon Son
- Lauren E. Mazurkiewicz (ORCID: https://orcid.org/0000-0002-8045-6803)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Wisconsin–Madison (US)
- Seoul National University (KR)
- Inserm (FR)
- Stockholm University (SE)
- Utrecht University (NL)
- Science for Life Laboratory (SE)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1083/jcb.202211035
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Burroughs Wellcome Fund
- University of Wisconsin-Madison
- National Research Foundation
- Seoul National University
- National Research Foundation of Korea
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Centre National de la Recherche Scientifique
- Grand Équipement National De Calcul Intensif
- École Normale Supérieure de Lyon
- National Institutes of Health
- Institut National de Physique Nucléaire et de Physique des Particules
- National Supercomputing Center, Korea Institute of Science and Technology Information