Structural basis for catalysis in a CDP-alcohol phosphotransferase

Giuliano Sciara, Oliver B. Clarke, David Tomasek, Brian Kloss, Shantelle Tabuso, Rushelle Byfield, Raphael Cohn, Surajit Banerjee, Kanagalaghatta R. Rajashankar, Vesna Slavkovic, Joseph H. Graziano, Lawrence Shapiro and Filippo Mancia ()
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Giuliano Sciara: Columbia University
Oliver B. Clarke: Columbia University
David Tomasek: Columbia University
Brian Kloss: New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Shantelle Tabuso: New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Rushelle Byfield: Columbia University
Raphael Cohn: Columbia University
Surajit Banerjee: Cornell University, NE-CAT, Advanced Photon Source
Kanagalaghatta R. Rajashankar: Cornell University, NE-CAT, Advanced Photon Source
Vesna Slavkovic: Mailman School of Public Health, Columbia University
Joseph H. Graziano: Mailman School of Public Health, Columbia University
Lawrence Shapiro: Columbia University
Filippo Mancia: Columbia University

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract The CDP-alcohol phosphotransferase (CDP-AP) family of integral membrane enzymes catalyses the transfer of a substituted phosphate group from a CDP-linked donor to an alcohol acceptor. This is an essential reaction for phospholipid biosynthesis across all kingdoms of life, and it is catalysed solely by CDP-APs. Here we report the 2.0 Å resolution crystal structure of a representative CDP-AP from Archaeoglobus fulgidus. The enzyme (AF2299) is a homodimer, with each protomer consisting of six transmembrane helices and an N-terminal cytosolic domain. A polar cavity within the membrane accommodates the active site, lined with the residues from an absolutely conserved CDP-AP signature motif (D1xxD2G1xxAR…G2xxxD3xxxD4). Structures in the apo, CMP-bound, CDP-bound and CDP-glycerol-bound states define functional roles for each of these eight conserved residues and allow us to propose a sequential, base-catalysed mechanism universal for CDP-APs, in which the fourth aspartate (D4) acts as the catalytic base.

Date: 2014
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DOI: 10.1038/ncomms5068

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