Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs

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

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.” Intrinsically disordered regions (IDRs) may serve as functional hubs to regulate protein functions. In this issue of Cell, Meyer et al. showed that disease-causing missense mutations in IDRs create dileucine motifs, which mediate clathrin-dependent trafficking that underlies disease etiology.

Original languageEnglish (US)
Pages (from-to)239-253.e17
Issue number1
StatePublished - Sep 20 2018


  • Glut1 deficiency syndrome
  • dileucine motif
  • endocytic trafficking
  • epilepsy
  • intrinsic disorder
  • mass spectrometry
  • point mutation
  • protein-protein interaction
  • proteomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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