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GTP-binding of ARL-3 is activated by ARL-13 as a GEF and stabilized by UNC-119

Qing Zhang1,2, Yan Li1,2, Yuxia Zhang1,2

  • 1Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Scientific Reports
|April 23, 2016
PubMed

Insights

Researchers discovered a new mechanism for activating small GTPase ARL-3, crucial for cilia formation. This involves ARL-13 acting as a GEF and UNC-119 stabilizing GTP binding, essential for ciliogenesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Primary cilia are vital sensory organelles for development.
  • Dysfunctional cilia, often due to ciliopathies, disrupt tissue formation.
  • The activation mechanisms of ciliary small GTPases, like ARLs, remain unclear.

Purpose of the Study:

  • To elucidate the activation mechanism of small GTPase ARL-3 in ciliogenesis.
  • To identify novel functional modules regulating ciliary small GTPases.
  • To understand the roles of ARL-13 and UNC-119 in cilia formation.

Main Methods:

  • Investigated a novel small GTPase module (ARL-3, ARL-13, UNC-119) in C. elegans.
  • Analyzed the synergistic and antagonistic interactions between ARL-13, UNC-119, and ARL-3.
  • Characterized the intrinsic GTP binding and GDP release rates of ARL-3.
  • Determined the GEF activity of ARL-13 and the stabilizing role of UNC-119 on ARL-3 GTP binding.

Main Results:

  • Identified a novel ARL-3, ARL-13, and UNC-119 functional module near the InV-like compartment.
  • ARL-13 acts as a GEF for ARL-3, while UNC-119 stabilizes ARL-3's GTP-bound state.
  • ARL-3 exhibits unique kinetics: high GDP release and low GTP binding rates.
  • Dysregulation of ARL-3 activation, particularly excess inactivated forms, impairs ciliogenesis.

Conclusions:

  • Revealed a novel regulatory mechanism for ciliogenesis involving ARL-13 and UNC-119.
  • ARL-13 acts as a GEF, coordinating with UNC-119 to activate ARL-3 for proper ciliogenesis.
  • This pathway is essential for maintaining ciliary function and preventing ciliopathies.

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