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National Institute of Environmental Health Sciences

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Publication Detail

Title: Structural basis for catalysis in a CDP-alcohol phosphotransferase.

Authors: Sciara, Giuliano; Clarke, Oliver B; Tomasek, David; Kloss, Brian; Tabuso, Shantelle; Byfield, Rushelle; Cohn, Raphael; Banerjee, Surajit; Rajashankar, Kanagalaghatta R; Slavkovic, Vesna; Graziano, Joseph H; Shapiro, Lawrence; Mancia, Filippo

Published In Nat Commun, (2014 Jun 13)

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 (D(1)xxD(2)G(1)xxAR...G(2)xxxD(3)xxxD(4)). 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.

PubMed ID: 24923293 Exiting the NIEHS site

MeSH Terms: Alcohols/metabolism*; Amino Acid Motifs; Amino Acid Sequence; Archaeal Proteins/chemistry*; Archaeal Proteins/genetics; Archaeal Proteins/metabolism; Archaeoglobus fulgidus/chemistry; Archaeoglobus fulgidus/enzymology*; Archaeoglobus fulgidus/genetics; Binding Sites; Biocatalysis; Catalytic Domain; Models, Molecular; Molecular Sequence Data; Phosphotransferases (Alcohol Group Acceptor)/chemistry*; Phosphotransferases (Alcohol Group Acceptor)/genetics; Phosphotransferases (Alcohol Group Acceptor)/metabolism; Protein Structure, Tertiary; Sequence Alignment

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