ZFIN ID: ZDB-PUB-120416-1
An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium
Wright, K.J., Baye, L.M., Olivier-Mason, A., Mukhopadhyay, S., Sang, L., Kwong, M., Wang, W., Pretorius, P.R., Sheffield, V.C., Sengupta, P., Slusarski, D.C., and Jackson, P.K.
Date: 2011
Source: Genes & Development   25(22): 2347-2360 (Journal)
Registered Authors: Baye, Lisa, Slusarski, Diane C.
Keywords: ARL3, NPHP, UNC119, myristoylation
MeSH Terms:
  • Adaptor Proteins, Signal Transducing*/genetics
  • Adaptor Proteins, Signal Transducing*/metabolism
  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans*/enzymology
  • Caenorhabditis elegans*/genetics
  • Caenorhabditis elegans*/metabolism
  • Caenorhabditis elegans Proteins/chemistry
  • Caenorhabditis elegans Proteins/metabolism
  • Cell Line
  • Cilia/enzymology
  • Cilia/metabolism*
  • GTP Phosphohydrolases/genetics
  • GTP Phosphohydrolases/metabolism*
  • Gene Knockdown Techniques
  • Intracellular Signaling Peptides and Proteins*/genetics
  • Intracellular Signaling Peptides and Proteins*/metabolism
  • Kinesin*/genetics
  • Kinesin*/metabolism
  • Monomeric GTP-Binding Proteins*/genetics
  • Monomeric GTP-Binding Proteins*/metabolism
  • Mutation
  • Phenotype
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Sequence Alignment
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 22085962 Full text @ Genes & Dev.

The membrane of the primary cilium is a highly specialized compartment that organizes proteins to achieve spatially ordered signaling. Disrupting ciliary organization leads to diseases called ciliopathies, with phenotypes ranging from retinal degeneration and cystic kidneys to neural tube defects. How proteins are selectively transported to and organized in the primary cilium remains unclear. Using a proteomic approach, we identified the ARL3 effector UNC119 as a binding partner of the myristoylated ciliopathy protein nephrocystin-3 (NPHP3). We mapped UNC119 binding to the N-terminal 200 residues of NPHP3 and found the interaction requires myristoylation. Creating directed mutants predicted from a structural model of the UNC119–myristate complex, we identified highly conserved phenylalanines within a hydrophobic β sandwich to be essential for myristate binding. Furthermore, we found that binding of ARL3-GTP serves to release myristoylated cargo from UNC119. Finally, we showed that ARL3, UNC119b (but not UNC119a), and the ARL3 GAP Retinitis Pigmentosa 2 (RP2) are required for NPHP3 ciliary targeting and that targeting requires UNC119b myristoyl-binding activity. Our results uncover a selective, membrane targeting GTPase cycle that delivers myristoylated proteins to the ciliary membrane and suggest that other myristoylated proteins may be similarly targeted to specialized membrane domains.