PXD067578-1

PXD067578 is an original dataset announced via ProteomeXchange.

Title	A Structural Mechanism for Noncanonical GPCR Signal Transduction in the Hedgehog Pathway
Description	The Hedgehog (Hh) signaling pathway is fundamental to embryogenesis, tissue homeostasis, and cancer. Hh signals are transduced via an unusual mechanism: upon agonist-induced phosphorylation, the noncanonical G protein-coupled receptor SMOOTHENED (SMO) binds the catalytic subunit of protein kinase A (PKA-C) and physically blocks its enzymatic activity. By combining computational structural approaches with biochemical and functional studies, we show that SMO mimics strategies prevalent in canonical GPCR and PKA signaling complexes, despite little sequence or secondary structural homology. An intrinsically disordered region of SMO binds the PKA-C active site, resembling the PKA regulatory subunit (PKA-R) / PKA-C holoenzyme, while the SMO transmembrane domain binds a conserved PKA-C interaction hub, similar to other GPCR-effector complexes. In contrast with prevailing GPCR signal transduction models, phosphorylation of SMO promotes intramolecular electrostatic interactions that stabilize key structural elements within the SMO cytoplasmic domain, thereby remodeling it into a PKA-inhibiting conformation. Our work provides a structural mechanism for a central step in the Hh cascade and defines a paradigm for disordered GPCR domains to transmit signals intracellularly.
HostingRepository	PRIDE
AnnounceDate	2026-03-26
AnnouncementXML	Submission_2026-03-26_12:26:04.588.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Varun Venkatakrishnan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-21 10:18:31	ID requested
⏵ 1	2026-03-26 12:26:05	announced

Dataset with its publication pending

submitter keyword: Smoothened, Protein Kinase A, Hedgehog

Benjamin Myers
contact affiliation	Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
contact email	benjamin.myers@hci.utah.edu
lab head
Varun Venkatakrishnan
contact affiliation	Dept. of Chemistry, Pennsylvania State University
contact email	vxv5106@psu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067578
     1. Label: PRIDE project
     2. Name: A Structural Mechanism for Noncanonical GPCR Signal Transduction in the Hedgehog Pathway