PXD010005

PXD010005 is an original dataset announced via ProteomeXchange.

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

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.

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]

curator keyword: Biological

submitter keyword: Glut1,disordered regions,PRM, Dileucin

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

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/2018/09/PXD010005

PRIDE project URI

• PRIDE
  1. PXD010005
     1. Label: PRIDE project
     2. Name: Mutations in disordered regions cause disease by creating dileucine motifs - PRM dataset-