Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
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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."
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- Authors
- Meyer, K., Kirchner, M., Uyar, B., Cheng, J.-Y., Russo, G., Hernandez-Miranda, L. R., Szymborska, A., Zauber, H., Rudolph, I.-M., Willnow, T. E., Akalin, A., Haucke, V., Gerhardt, H., Birchmeier, C., Kühn, R., Krauss, M., Diecke, S., Pascual, J. M., & Selbach, M.
- Affiliations
- Max Delbrück Center (DE)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Selbach, Matthias
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 175
- Issue
- 1
- Pages
- 239-253.e17
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2891753225
- Cited by
- 132
- References
- 4
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 15 · 2023: 15 · 2022: 17 · 2021: 22 · 2020: 19 · 2019: 15 · 2018: 4
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- National Institutes of Health (NS077015, NS094257)
- Deutsche Forschungsgemeinschaft (SFB958/A11)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- intrinsically disordered regions, missense mutations, dileucine motif, protein mislocalization, GLUT1, GLUT1 deficiency syndrome, IP3R1, CACNA1H, transmembrane proteins, protein-protein interaction, pathogenic variants
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Carbohydrate Metabolism, Inborn Errors, Clathrin, Cytoplasm, Humans, Leucine, Membrane Proteins, Mice, Inbred C57BL, Monosaccharide Transport Proteins, Mutation, Peptides, Protein Binding, Calcium Channels, T-Type, Amino Acid Motifs, Proteomics, Glucose Transporter Type 1, Mice, Inositol 1,4,5-Trisphosphate Receptors, Intrinsically Disordered Proteins
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