Abstract
The C. elegans proteins PAQR-2 (a homolog of the human seven-transmembrane domain AdipoR1 and AdipoR2 proteins) and IGLR-2 (a homolog of the mammalian LRIG proteins characterized by a single transmembrane domain and the presence of immunoglobulin domains and leucine-rich repeats in their extracellular portion) form a complex that protects against plasma membrane rigidification by promoting the expression of fatty acid desaturases and the incorporation of polyunsaturated fatty acids into phospholipids, hence increasing membrane fluidity. In the present study, we leveraged a novel gain-of-function allele of PAQR-1, a PAQR-2 paralog, to carry out structure-function studies. We found that the transmembrane domains of PAQR-2 are responsible for its functional requirement for IGLR-2, that PAQR-1 does not require IGLR-2 but acts via the same pathway as PAQR-2, and that the divergent N-terminal cytoplasmic domains of the PAQR-1 and PAQR-2 proteins serve a regulatory function and may regulate access to the catalytic site of these proteins. We also show that overexpression of human AdipoR1 or AdipoR2 alone is sufficient to confer increased palmitic acid resistance in HEK293 cells, and thus act in a manner analogous to the PAQR-1 gain-of-function allele.
Highlights
Maintenance of cell membrane homeostasis relies on regulatory proteins that sense and respond to properties such as lipid composition, thickness, compressibility, lateral mobility and curvature [1, 2]
We focus on a small group of proteins found in all animals, and called AdipoR1 and AdipoR2 in humans, and PAQR-1 and PAQR-2 in the worm Caenorhabditis elegans
We found a version of PAQR-1 that is more “active”, and promotes increased levels of unsaturated fats in membranes
Summary
Maintenance of cell membrane homeostasis relies on regulatory proteins that sense and respond to properties such as lipid composition, thickness, compressibility, lateral mobility and curvature [1, 2]. The best understood example is perhaps the bacterial multi-pass protein DesK that undergoes a conformational change in response to increased membrane rigidification, resulting in the activation of its kinase domain [3,4,5,6]. The yeast single-pass plasma membrane protein Mga rotates along its long axis when the surrounding acyl chains are densely packed, resulting in its activation [7]. We identified a novel regulator of membrane homeostasis in animal cells, namely the PAQR-2/IGLR-2 complex in the nematode C. elegans [13,14,15,16,17,18]. The present work helps define the structure-functional basis of fluidity sensing by this complex
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