Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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

Supplementary concepts

  • Glut1 Deficiency Syndrome