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Cell. 2018 Sep 20;175(1):239-253.e17. doi: 10.1016/j.cell.2018.08.019. Epub 2018 Sep 6.

Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs.

Author information

1
Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
2
Bioinformatics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
3
Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
4
Developmental Biology/Signal Transduction, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
5
Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research) partner site, 13347 Berlin, Germany.
6
Molecular Cardiovascular Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
7
Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; DZHK (German Centre for Cardiovascular Research) partner site, 13347 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
8
Berlin Institute of Health (BIH), 10178 Berlin, Germany; Core Facility Transgenics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
9
DZHK (German Centre for Cardiovascular Research) partner site, 13347 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Core Facility Pluripotent Stem Cells, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
10
Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390, USA.
11
Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: matthias.selbach@mdc-berlin.de.

Abstract

Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but 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 clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. 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."

KEYWORDS:

Glut1 deficiency syndrome; dileucine motif; endocytic trafficking; epilepsy; intrinsic disorder; mass spectrometry; point mutation; protein-protein interaction; proteomics

PMID:
30197081
DOI:
10.1016/j.cell.2018.08.019
[Indexed for MEDLINE]
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