Development of a nanoscale protein-protein mapping of PDE4 interface-disrupting peptides
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Spatially confined β-adrenergic receptor-cAMP nanodomain signaling depends on scaffolded
protein-protein interactions (PPIs), yet converting such nano-interfaces into cell-active disruptor
peptides remains challenging. Here, we identify a previously unrecognized phosphodiesterase 4A
(PDE4A)-filamin A complex in human cardiac tissue that is disrupted in dilated cardiomyopathy.
To target this interaction, we developed a nanodomain-resolved AlphaFold3 workflow integrating
interface-recurrence filtering, orthogonal docking, and peptide-binding site inference to define a
tractable binding region. This approach identified a filamin A docking sequence spanning R2520
H2528, which was optimized to RLVSNHSLH and rendered cell-permeant by N-terminal
polyarginine tagging. In ventricular cardiomyocytes, the peptide reduced PDE4A-filamin A
proximity and selectively attenuated β-adrenergic cAMP signaling in cytosolic and sarcolemmal
compartments, measured by FRET biosensors. This work establishes a potential transferable
strategy for translating predicted scaffolded PPI nano-interfaces into functional disruptor peptides
and highlights compartmentalized signaling complexes as actionable targets for selective cellular
modulation.
protein-protein interactions (PPIs), yet converting such nano-interfaces into cell-active disruptor
peptides remains challenging. Here, we identify a previously unrecognized phosphodiesterase 4A
(PDE4A)-filamin A complex in human cardiac tissue that is disrupted in dilated cardiomyopathy.
To target this interaction, we developed a nanodomain-resolved AlphaFold3 workflow integrating
interface-recurrence filtering, orthogonal docking, and peptide-binding site inference to define a
tractable binding region. This approach identified a filamin A docking sequence spanning R2520
H2528, which was optimized to RLVSNHSLH and rendered cell-permeant by N-terminal
polyarginine tagging. In ventricular cardiomyocytes, the peptide reduced PDE4A-filamin A
proximity and selectively attenuated β-adrenergic cAMP signaling in cytosolic and sarcolemmal
compartments, measured by FRET biosensors. This work establishes a potential transferable
strategy for translating predicted scaffolded PPI nano-interfaces into functional disruptor peptides
and highlights compartmentalized signaling complexes as actionable targets for selective cellular
modulation.
Date Acceptance
2026-06-17
Citation
Nano Letters
ISSN
1530-6984
Publisher
American Chemical Society
Journal / Book Title
Nano Letters
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
License URL
Publication Status
Accepted