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PXD010027

PXD010027 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMutations in disordered regions cause disease by creating dileucine motifs - peptide-protein interaction screen
DescriptionMany disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins. Since these mutations do not affect protein structure, the molecular mechanism of their pathogenicity is enigmatic. 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_04:45:30.600.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterKatrina Meyer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-06-05 00:15:54ID requested
12018-09-13 00:38:44announced
22024-10-22 04:45:38announced2024-10-22: 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: Biomedical
submitter keyword: peptide array, PPI,protein-protein interaction, disordered regions
Contact List
Matthias Selbach
contact affiliationProteome Dynamics, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, D-13092 Berlin, Germany Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
contact emailmatthias.selbach@mdc-berlin.de
lab head
Katrina Meyer
contact affiliationMDC
contact emailkatrina.meyer@mdc-berlin.de
dataset submitter
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