Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space
Fabio Lolicato1,2, Julia P Steringer1, Roberto Saleppico1
1Heidelberg University Biochemistry Center, Heidelberg, Germany.
Elife
|January 22, 2024
Summary
Fibroblast growth factor 2 (FGF2) secretion involves membrane pore formation. Disulfide-bridged FGF2 dimers, formed via C95, are key to oligomerization, pore creation, and FGF2 translocation across cell membranes.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Fibroblast growth factor 2 (FGF2) is secreted via unconventional protein secretion.
- FGF2 translocation across the plasma membrane requires PI(4,5)P2 and cell surface GPC1.
- The molecular mechanism of FGF2 oligomerization during secretion is not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism of FGF2 oligomerization and membrane translocation.
- To investigate the role of cysteine residues (C95 and C77) in FGF2 secretion.
- To understand the interaction of FGF2 with the Na,K-ATPase.
Main Methods:
- Site-directed mutagenesis (C95A substitution).
- Cross-linking mass spectrometry.
- Atomistic molecular dynamics simulations and machine learning analysis.
- Cryo-electron tomography.
Main Results:
- FGF2 oligomerization is initiated by C95-C95 disulfide-bridge-mediated dimerization on membrane surfaces.
- C95A substitution disrupts FGF2 oligomerization, pore formation, and membrane translocation, leading to a severe secretion defect.
- C77 is involved in binding to the Na,K-ATPase but not FGF2 oligomerization.
- Disulfide-bridged FGF2 dimers bind avidly to PI(4,5)P2, initiating pore formation.
Conclusions:
- C95-mediated disulfide-bridged FGF2 dimers are essential building blocks for FGF2 oligomerization and secretion.
- FGF2 secretion is tightly coupled to the formation of signaling complexes, with C95-bridged dimers potentially triggering autocrine/paracrine signaling.
Keywords:
E. coliFGF2Protein traffickingProtein-lipid interactionProtein-protein interactionUnconventional protein secretionbiochemistrychemical biologychocho k1hela s3More Related Videos
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