PXD043523 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Cullin-RING ligases target substrates with geometrically optimized catalytic partners |
Description | Cullin-RING ubiquitin ligases (CRLs) control the degradation of a wide landscape of human proteins in combination with ubiquitin-carrying enzymes (UCEs). CRL expansion during evolution is apparent, with a few dozen in yeast that function with a single UCE and as many as 300 in humans that function with at least 8 UCEs. A major unaddressed question is why human CRL buildup has been accompanied by additional UCEs that function with CRLs. Here we demonstrate that human CRLs and UCEs can display specificity, resulting in increased affinity for each other and enhanced rates of ubiquitin transfer to substrates. To uncover the structural basis for CRL-UCE specificity, cryo-EM was performed on a CRL2 subfamily member with substrate receptor subunit FEM1C (CRL2FEM1C) in complex with a proxy for catalytically active UCE. The structure elucidated an extensive CRL-UCE interface that promotes proximity between the UCE active site and CRL2FEM1C-bound substrate. Unanticipated selectivity was also observed between the CRL substrate Lys ubiquitylation sites and the identity of the UCE. CRL-UCE specificity also manifests during targeted protein degradation by affecting the activities of drugs that induce ubiquitylation of neosubstrates. An emerging CRL code is revealed that drives selective formation of CRL-UCE complexes to promote rapid substrate ubiquitylation. |
HostingRepository | PRIDE |
AnnounceDate | 2024-05-22 |
AnnouncementXML | Submission_2024-05-22_11:53:59.316.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Barbara Steigenberger |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | ubiquitinylated lysine |
Instrument | Orbitrap Fusion Lumos; Orbitrap Exploris 480 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-07-04 02:07:11 | ID requested | |
⏵ 1 | 2024-05-22 11:54:00 | announced | |
Publication List
10.1016/j.molcel.2024.01.022; |
Li J, Purser N, Liwocha J, Scott DC, Byers HA, Steigenberger B, Hill S, Tripathi-Giesgen I, Hinkle T, Hansen FM, Prabu JR, Radhakrishnan SK, Kirkpatrick DS, Reichermeier KM, Schulman BA, Kleiger G, Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting. Mol Cell, 84(7):1304-1320.e16(2024) [pubmed] |
Keyword List
submitter keyword: ubiquitylation,Cullin-RING ligase |
Contact List
Brenda A. |
contact affiliation | Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany |
contact email | schulman@biochem.mpg.de |
lab head | |
Barbara Steigenberger |
contact affiliation | MPI of Biochemistry |
contact email | steigenberger@biochem.mpg.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD043523
- Label: PRIDE project
- Name: Cullin-RING ligases target substrates with geometrically optimized catalytic partners