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

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."

• Authors: Katrina Meyer, Marieluise Kirchner, Bora Uyar, Jing-Yuan Cheng, Giulia Russo, Luis R Hernandez-Miranda, Anna Szymborska, Henrik Zauber, Ina-Maria Rudolph, Thomas E Willnow, Altuna Akalin, Volker Haucke, Holger Gerhardt, Carmen Birchmeier, Ralf Kühn, Michael Krauss, Sebastian Diecke, Juan M Pascual, Matthias Selbach
• Journal: Cell (Cell) Vol. 175 Issue 1 Pg. 239-253.e17 (09 20 2018) ISSN: 1097-4172 [Electronic] United States
• PMID: 30197081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Cacna1h protein, mouse
• Calcium Channels, T-Type
• Clathrin
• Glucose Transporter Type 1
• Inositol 1,4,5-Trisphosphate Receptors
• Intrinsically Disordered Proteins
• Itpr1 protein, mouse
• Membrane Proteins
• Monosaccharide Transport Proteins
• Peptides
• SLC2A1 protein, human
• Leucine

Topics

• Amino Acid Motifs (genetics)
• Amino Acid Sequence
• Animals
• Binding Sites
• Calcium Channels, T-Type (genetics, physiology)
• Carbohydrate Metabolism, Inborn Errors
• Clathrin (metabolism)
• Cytoplasm (metabolism)
• Glucose Transporter Type 1 (genetics, metabolism, physiology)
• Humans
• Inositol 1,4,5-Trisphosphate Receptors (genetics, physiology)
• Intrinsically Disordered Proteins (genetics, metabolism, physiology)
• Leucine (metabolism)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Monosaccharide Transport Proteins (deficiency)
• Mutation (genetics)
• Peptides
• Protein Binding
• Proteomics (methods)