PXD043523

PXD043523 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-04 02:07:11	ID requested
⏵ 1	2024-05-22 11:54:00	announced

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]

submitter keyword: ubiquitylation,Cullin-RING ligase

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

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/2024/05/PXD043523

PRIDE project URI

• PRIDE
  1. PXD043523
     1. Label: PRIDE project
     2. Name: Cullin-RING ligases target substrates with geometrically optimized catalytic partners