A synergy between mechanosensitive calcium- and membrane-binding mediates tension-sensing by C2-like domains

When nuclear membranes are stretched, the peripheral membrane enzyme cytosolic phospholipase A2 (cPLA ) binds via its calcium-dependent C2 domain (cPLA -C2) and initiates bioactive lipid signaling and tissue inflammation. More than 150 C2-like domains are encoded in vertebrate genomes. How many of t...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 1
Main Authors Shen, Zhouyang, Belcheva, Kalina T, Jelcic, Mark, Hui, King Lam, Katikaneni, Anushka, Niethammer, Philipp
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.01.2022
Subjects
Antibodies
Binding
Biological Sciences
Calcium
Calcium ions
Domains
Genomes
Group IV Phospholipases A2 - chemistry
Humans
Hydrophobicity
Lipid bilayers
Lipid Bilayers - chemistry
Lipids
Mechanotransduction
Mechanotransduction, Cellular
Membranes
Nuclear Envelope - chemistry
Nuclear membranes
Phospholipase A2
Protein Domains
Surface Tension
Vertebrates
cPLA2
nucleus
calcium
membrane
mechanotransduction
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Summary:When nuclear membranes are stretched, the peripheral membrane enzyme cytosolic phospholipase A2 (cPLA ) binds via its calcium-dependent C2 domain (cPLA -C2) and initiates bioactive lipid signaling and tissue inflammation. More than 150 C2-like domains are encoded in vertebrate genomes. How many of them are mechanosensors and quantitative relationships between tension and membrane recruitment remain unexplored, leaving a knowledge gap in the mechanotransduction field. In this study, we imaged the mechanosensitive adsorption of cPLA and its C2 domain to nuclear membranes and artificial lipid bilayers, comparing it to related C2-like motifs. Stretch increased the Ca sensitivity of all tested domains, promoting half-maximal binding of cPLA at cytoplasmic resting-Ca concentrations. cPLA -C2 bound up to 50 times tighter to stretched than to unstretched membranes. Our data suggest that a synergy of mechanosensitive Ca interactions and deep, hydrophobic membrane insertion enables cPLA -C2 to detect stretched membranes with antibody-like affinity, providing a quantitative basis for understanding mechanotransduction by C2-like domains.
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Edited by James Hurley, Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, University of California, Berkeley, CA; received July 5, 2021; accepted November 19, 2021
Author contributions: Z.S. and P.N. designed the research; Z.S. and K.T.B. performed the research; Z.S., M.J., K.L.H., A.K., and P.N. contributed new reagents/analytic tools; Z.S. and P.N. analyzed the data; and Z.S. and P.N. wrote the paper.
2Present address: University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27705.
1Present address: Fate Therapeutics, Inc., San Diego, CA 92121.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2112390119