Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains

Alexandru Zabara, Josephine Tse Yin Chong, Isabelle Martiel, Laura Stark, Brett A. Cromer, Chiara Speziale, Calum John Drummond and Raffaele Mezzenga ()
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Alexandru Zabara: ETH Zurich
Josephine Tse Yin Chong: ETH Zurich
Isabelle Martiel: Paul Scherrer Institute
Laura Stark: University of Western Australia
Brett A. Cromer: RMIT University
Chiara Speziale: ETH Zurich
Calum John Drummond: RMIT University
Raffaele Mezzenga: ETH Zurich

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract In meso crystallization of membrane proteins from lipidic mesophases is central to protein structural biology but limited to membrane proteins with small extracellular domains (ECDs), comparable to the water channels (3–5 nm) of the mesophase. Here we present a strategy expanding the scope of in meso crystallization to membrane proteins with very large ECDs. We combine monoacylglycerols and phospholipids to design thermodynamically stable ultra-swollen bicontinuous cubic phases of double-gyroid (Ia3d), double-diamond (Pn3m), and double-primitive (Im3m) space groups, with water channels five times larger than traditional lipidic mesophases, and showing re-entrant behavior upon increasing hydration, of sequences Ia3d→Pn3m→Ia3d and Pn3m→Im3m→Pn3m, unknown in lipid self-assembly. We use these mesophases to crystallize membrane proteins with ECDs inaccessible to conventional in meso crystallization, demonstrating the methodology on the Gloeobacter ligand-gated ion channel (GLIC) protein, and show substantial modulation of packing, molecular contacts and activation state of the ensued proteins crystals, illuminating a general strategy in protein structural biology.

Date: 2018
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DOI: 10.1038/s41467-018-02996-5

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