Structure of the polyisoprenyl-phosphate glycosyltransferase GtrB and insights into the mechanism of catalysis

Chiara Ardiccioni, Oliver B. Clarke, David Tomasek, Habon A. Issa, Desiree C. von Alpen, Heather L. Pond, Surajit Banerjee, Kanagalaghatta R. Rajashankar, Qun Liu, Ziqiang Guan, Chijun Li, Brian Kloss, Renato Bruni, Edda Kloppmann, Burkhard Rost, M. Chiara Manzini, Lawrence Shapiro and Filippo Mancia ()
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Chiara Ardiccioni: Columbia University
Oliver B. Clarke: Columbia University
David Tomasek: Columbia University
Habon A. Issa: George Washington University
Desiree C. von Alpen: George Washington University
Heather L. Pond: George Washington University
Surajit Banerjee: Cornell University, Argonne National Laboratory
Kanagalaghatta R. Rajashankar: Cornell University, Argonne National Laboratory
Qun Liu: New York Structural Biology Center, X4 Beamlines, Brookhaven National Laboratory
Ziqiang Guan: Duke University Medical Center
Chijun Li: Duke University Medical Center
Brian Kloss: New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Renato Bruni: New York Consortium on Membrane Protein Structure, New York Structural Biology Center
Edda Kloppmann: Bioinformatics and Computational Biology
Burkhard Rost: Bioinformatics and Computational Biology
M. Chiara Manzini: George Washington University
Lawrence Shapiro: Columbia University
Filippo Mancia: Columbia University

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract The attachment of a sugar to a hydrophobic polyisoprenyl carrier is the first step for all extracellular glycosylation processes. The enzymes that perform these reactions, polyisoprenyl-glycosyltransferases (PI-GTs) include dolichol phosphate mannose synthase (DPMS), which generates the mannose donor for glycosylation in the endoplasmic reticulum. Here we report the 3.0Å resolution crystal structure of GtrB, a glucose-specific PI-GT from Synechocystis, showing a tetramer in which each protomer contributes two helices to a membrane-spanning bundle. The active site is 15 Å from the membrane, raising the question of how water-soluble and membrane-embedded substrates are brought into apposition for catalysis. A conserved juxtamembrane domain harbours disease mutations, which compromised activity in GtrB in vitro and in human DPM1 tested in zebrafish. We hypothesize a role of this domain in shielding the polyisoprenyl-phosphate for transport to the active site. Our results reveal the basis of PI-GT function, and provide a potential molecular explanation for DPM1-related disease.

Date: 2016
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DOI: 10.1038/ncomms10175

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