PXD037899 is an
original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Cellular determinants of targeted membrane protein degradation by lysosome targeting chimeras |
| Description | Targeted protein degradation is a powerful therapeutic strategy that offers benefits over canonical target inhibition. Lysosome targeting chimeras (LYTACs) harness lysosome trafficking receptors such as the cation-independent mannose-6-phosphate receptor (CI-M6PR) to direct secreted and membrane proteins to lysosomes. Their development as therapeutics would benefit from mechanistic insights into the factors that govern their activity. We conducted a genome-wide CRISPR screen to identify modulators of LYTAC-mediated membrane protein degradation. Disrupting retromer genes improved LYTAC-induced degradation by reducing the recycling of LYTAC-CI-M6PR complexes from endosomes to the plasma membrane. We identified neddylated cullin 3 as a predictive marker for LYTAC efficacy. Quantitative proteomics revealed that a significant fraction of cell-surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Accordingly, disruption of M6P biosynthesis enhanced the internalization of LYTAC-target complexes. Our findings inform new design strategies for LYTACs with enhanced degradation activity and elucidate the biology of CI-M6PR with implications for enzyme replacement therapies. |
| HostingRepository | PRIDE |
| AnnounceDate | 2024-01-26 |
| AnnouncementXML | Submission_2024-01-26_07:02:18.365.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Nicholas Riley |
| SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
| ModificationList | No PTMs are included in the dataset |
| Instrument | Orbitrap Fusion |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|
| 0 | 2022-11-03 04:10:12 | ID requested | |
| ⏵ 1 | 2024-01-26 07:02:19 | announced | |
| 2 | 2024-10-22 06:25:54 | announced | 2024-10-22: Updated project metadata. |
Publication List
| Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, Bassik MC, Banik SM, Bertozzi CR, Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science, 382(6668):eadf6249(2023) [pubmed] |
| 10.1126/science.adf6249; |
Keyword List
| submitter keyword: DIA, LYTAC, quantitative proteomics,lysosome, CRISPRi |
Contact List
| Carolyn Bertozzi |
|---|
| contact affiliation | Department of Chemistry and Sarafan ChEM-H |
| contact email | bertozzi@stanford.edu |
| lab head | |
| Nicholas Riley |
|---|
| contact affiliation | Stanford University |
| contact email | riley.nicholasm@gmail.com |
| dataset submitter | |
Full Dataset Link List
Dataset FTP location
NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD037899 |
| PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD037899
- Label: PRIDE project
- Name: Cellular determinants of targeted membrane protein degradation by lysosome targeting chimeras
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