Cryo-EM structures reveal the mechanism of phosphatidylserine remodeling by membrane-bound glycerophospholipid O-acyltransferase 1
Lands cycle remodeling of glycerophospholipid acyl chains is crucial for cells to maintain appropriate membrane composition. Glycerophospholipids are cleaved at the glycerol sn2-position by phospholipase A. The lysophospholipids are reacylated by enzymes of the membrane-bound O-acyltransferase (MBOAT) family to incorporate specific fatty-acyl chains to adjust membrane properties. How MBOAT…
Membrane-bound glycerophospholipid O-acyltransferase 1 (MBOAT1) is essential for cells to maintain proper membrane composition. MBOAT1 cleaves glycerophospholipids at the glycerol sn2-position, creating lysophospholipids that are then reacylated by enzymes to incorporate specific fatty-acyl chains, adjusting membrane properties.
The process of MBOAT1 recognizing specific acyl-CoA donors, selecting lysophospholipid acceptors, and releasing products remains unclear. Phosphatidylserine (PS), an anionic phospholipid, influences membrane surface charge, protein recruitment, and cell death-associated membrane recognition. PS acyl-chain remodeling is also associated with ferroptosis resistance.
Researchers revealed that MBOAT1 preferentially generates monounsaturated fatty acid-containing PS from lyso-PS. To understand the mechanism and pathway of MBOAT1-dependent PS remodeling, they employed high-resolution cryo-electron microscopy structures of human MBOAT1. These structures displayed distinct binding poses of the fatty acyl donor, lyso-PS acceptor, and PS product. Using lipidomics, enzymology, and molecular dynamics simulations, the team uncovered the mechanism and pathway of MBOAT1-dependent PS remodeling.
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