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Mutations in disordered regions can cause disease by creating dileucine motifs

Item Type:Article
Title:Mutations in disordered regions can cause disease by creating dileucine motifs
Creators Name:Meyer, K. and Kirchner, M. and Uyar, B. and Cheng, J.Y. and Russo, G. and Hernandez-Miranda, L.R. and Szymborska, A. and Zauber, H. and Rudolph, I.M. and Willnow, T.E. and Akalin, A. and Haucke, V. and Gerhardt, H. and Birchmeier, C. and Kühn, R. and Krauss, M. and Diecke, S. and Pascual, J.M. and Selbach, M.
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:Protein-Protein Interaction, Intrinsic Disorder, Dileucine Motif, Endocytic Trafficking, Mass Spectrometry, Proteomics, Point Mutation, Glut1 Deficiency Syndrome, Epilepsy, Animals, Mice
Source:Cell
ISSN:0092-8674
Publisher:Elsevier / Cell Press (U.S.A.)
Volume:175
Number:1
Page Range:239-253.e17
Date:20 September 2018
Official Publication:https://doi.org/10.1016/j.cell.2018.08.019
PubMed:View item in PubMed

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