Triaging of α-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology
Open accessPublished version of a preprint
Abstract
Mitochondrial outer membrane α-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse substrates remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse α-helical substrates reveals that these components are organized into distinct targeting pathways which act on substrates based on their topology. NAC is required for efficient targeting of polytopic proteins whereas signal-anchored proteins require TTC1, a novel cytosolic chaperone which physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation
Gilbert, L. A., Horlbeck, M. A., Adamson, B., Villalta, J. E., Chen, Y., Whitehead, E. H., Guimaraes, C., Panning, B., Ploegh, H. L., Bassik, M. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.029 · Cited by 2,728 · see citing works
Self-citationStructure of TPR Domain–Peptide Complexes
Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., Bartunik, H., Hartl, F. U., & Moarefi, I. (2000) · Cell · doi:10.1016/s0092-8674(00)80830-2 · Cited by 1,188 · see citing works
Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes.
Rapoport, T. A. (2007) · Nature · doi:10.1038/nature06384 · Cited by 977 · see citing works
Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq
Replogle, J. M., Saunders, R. A., Pogson, A. N., Hussmann, J. A., Lenail, A., Guna, A., Mascibroda, L., Wagner, E. J., Adelman, K., Lithwick-Yanai, G., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.013 · Cited by 751 · see citing works
Self-citationHung, V., Zou, P., Rhee, H.-W., Udeshi, N. D., Cracan, V., Svinkina, T., Carr, S. A., Mootha, V. K., & Ting, A. Y. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.003 · Cited by 517 · see citing works
Protein translocation across biological membranes
Wickner, W., & Schekman, R. (2005) · Science · doi:10.1126/science.1113752 · Cited by 458 · see citing works
Protein-protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis
Liu, J., Rone, M. B., & Papadopoulos, V. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608820200 · Cited by 241 · see citing works
Chen, J. J., Nathaniel, D. L., Raghavan, P., Nelson, M., Tian, R., Tse, E., Hong, J. Y., See, S. K., Mok, S.-A., Hein, M. Y., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009432 · Cited by 170 · see citing works
Flagged first, then by citations
- Authors
- Muthukumar, G., Stevens, T. A., Inglis, A. J., Esantsi, T. K., Saunders, R. A., Schulte, F., Voorhees, R. M., Guna, A., & Weissman, J. S.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- California Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Guna, Alina
- Weissman, Jonathan S.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2024-03
- Volume
- 84
- Issue
- 6
- Pages
- 1101-1119.e9
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC10462106
- OpenAlex
- W4392302547
- Cited by
- 34
- References
- 9
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 2
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- HHMI
- Human Frontier Science Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial outer membrane, alpha-helical membrane proteins, protein targeting, protein insertion, molecular chaperones, NAC, TPR domain, polytopic membrane proteins, membrane topology, mitochondrial biogenesis, CRISPRi screen
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
