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Mutations in disordered regions cause disease by creating endocytosis motifs

Item Type:Preprint
Title:Mutations in disordered regions cause disease by creating endocytosis motifs
Creators Name:Meyer, K. and Uyar, B. and Kirchner, M. and Cheng, J. and Akalin, A. and Selbach, M.
Abstract:Mutations in intrinsically disordered regions (IDRs) of proteins can cause a wide spectrum of diseases. Since IDRs lack a fixed three-dimensional structure, the mechanism by which such mutations cause disease is often unknown. Here, we employ a 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 clathrins. In all three cases, the mutation creates a dileucine motif known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), a glucose transporter involved in GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in cytosolic tails of transmembrane proteins. Dileucine motif gains thus appear to be a recurrent cause of disease.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:141622
Date:24 May 2017
Official Publication:https://doi.org/10.1101/141622

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