PXD010005 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Mutations in disordered regions cause disease by creating dileucine motifs - PRM dataset- |
Description | Mutations in intrinsically disordered regions (IDRs) of proteins are associated with a wide spectrum of diseases. Since IDRs lack a fixed three-dimensional structure, the molecular mechanism by which such mutations cause disease is often unknown. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1 and CACNA1H) lead to an increased binding of clathrin. In all three cases, the mutation creates a dileucine motif known to mediate clathrin-dependent trafficking. Follow-up experiments on full length GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments in a model cell line and in patient-derived induced pluripotent stem cells. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking-down AP-2 reverts the cellular mislocalization. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause “dileucineopathies”. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_04:44:51.455.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Henrik Zauber |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2018-06-01 08:34:42 | ID requested | |
1 | 2018-09-13 00:41:42 | announced | |
⏵ 2 | 2024-10-22 04:44:52 | announced | 2024-10-22: Updated project metadata. |
Publication List
10.1016/j.cell.2018.08.019; |
Meyer K, Kirchner M, Uyar B, Cheng JY, Russo G, Hernandez-Miranda LR, Szymborska A, Zauber H, Rudolph IM, Willnow TE, Akalin A, Haucke V, Gerhardt H, Birchmeier C, K, ü, hn R, Krauss M, Diecke S, Pascual JM, Selbach M, Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs. Cell, 175(1):239-253.e17(2018) [pubmed] |
Keyword List
curator keyword: Biological |
submitter keyword: Glut1,disordered regions,PRM, Dileucin |
Contact List
Matthias Selbach |
contact affiliation | Proteome Dynamics MDC in the helmholtz association Berlin-Buch |
contact email | matthias.selbach@mdc-berlin.de |
lab head | |
Henrik Zauber |
contact affiliation | MDC Berlin-Buch |
contact email | henrik.zauber@mdc-berlin.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD010005
- Label: PRIDE project
- Name: Mutations in disordered regions cause disease by creating dileucine motifs - PRM dataset-