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A Structural Mechanism for Noncanonical GPCR Signal Transduction in the Hedgehog Pathway.

William P Steiner1,2,3, Nathan Iverson1,2,3, Varun Venkatakrishnan1,2,3

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The Hedgehog (Hh) pathway uses SMO protein to block protein kinase A (PKA) activity through a unique structural mechanism. This study reveals how SMO

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • The Hedgehog (Hh) signaling pathway is crucial for embryonic development, tissue maintenance, and cancer progression.
  • Signal transduction involves the G protein-coupled receptor SMOOTHENED (SMO) interacting with protein kinase A (PKA).

Purpose of the Study:

  • To elucidate the structural mechanism by which SMO inhibits PKA activity.
  • To understand the role of SMO phosphorylation in Hh signal transduction.
  • To explore how disordered GPCR domains transmit intracellular signals.

Main Methods:

  • Computational structural modeling.
  • Biochemical assays.
  • Functional studies.

Main Results:

  • SMO utilizes strategies similar to canonical GPCRs and PKA complexes despite low homology.
  • An intrinsically disordered SMO region binds PKA's active site, mimicking PKA-R.
  • SMO phosphorylation induces intramolecular interactions, forming a PKA-inhibiting conformation.

Conclusions:

  • A structural mechanism for SMO-mediated PKA inhibition in the Hh pathway is defined.
  • Disordered GPCR domains can adopt specific conformations to transmit signals.
  • This provides insights into Hh pathway regulation and GPCR signaling.