Details

Autor(en) / Beteiligte

• Meyer, Katrina
• Kirchner, Marieluise
• Uyar, Bora
• Cheng, Jing-Yuan
• Russo, Giulia
• Hernandez-Miranda, Luis R.
• Szymborska, Anna
• Zauber, Henrik
• Rudolph, Ina-Maria
• Willnow, Thomas E.
• Akalin, Altuna
• Haucke, Volker
• Gerhardt, Holger
• Birchmeier, Carmen
• Kühn, Ralf
• Krauss, Michael
• Diecke, Sebastian
• Pascual, Juan M.
• Selbach, Matthias

Titel

Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs

Ist Teil von

• Cell, 2018-09, Vol.175 (1), p.239-253.e17

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.” [Display omitted] •A peptide-based screen detects how mutations affect protein-protein interactions•Several pathogenic mutations create dileucine motifs and recruit clathrin•A dileucine motif gain in GLUT1 causes mistrafficking in GLUT1 deficiency syndrome•Protein mistrafficking via dileucine motif gains is a recurrent cause of disease 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.