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PXD010005

PXD010005 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMutations in disordered regions cause disease by creating dileucine motifs - PRM dataset-
DescriptionMutations 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”.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_04:44:51.455.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterHenrik Zauber
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-06-01 08:34:42ID requested
12018-09-13 00:41:42announced
22024-10-22 04:44:52announced2024-10-22: 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 affiliationProteome Dynamics MDC in the helmholtz association Berlin-Buch
contact emailmatthias.selbach@mdc-berlin.de
lab head
Henrik Zauber
contact affiliationMDC Berlin-Buch
contact emailhenrik.zauber@mdc-berlin.de
dataset submitter
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Dataset FTP location
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PRIDE project URI
Repository Record List
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