Structural basis for dolichylphosphate mannose biosynthesis

Rosaria Gandini, Tom Reichenbach, Tien-Chye Tan and Christina Divne ()
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Rosaria Gandini: KTH Royal Institute of Technology
Tom Reichenbach: KTH Royal Institute of Technology
Tien-Chye Tan: KTH Royal Institute of Technology
Christina Divne: KTH Royal Institute of Technology

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Protein glycosylation is a critical protein modification. In biogenic membranes of eukaryotes and archaea, these reactions require activated mannose in the form of the lipid conjugate dolichylphosphate mannose (Dol-P-Man). The membrane protein dolichylphosphate mannose synthase (DPMS) catalyzes the reaction whereby mannose is transferred from GDP-mannose to the dolichol carrier Dol-P, to yield Dol-P-Man. Failure to produce or utilize Dol-P-Man compromises organism viability, and in humans, several mutations in the human dpm1 gene lead to congenital disorders of glycosylation (CDG). Here, we report three high-resolution crystal structures of archaeal DPMS from Pyrococcus furiosus, in complex with nucleotide, donor, and glycolipid product. The structures offer snapshots along the catalytic cycle, and reveal how lipid binding couples to movements of interface helices, metal binding, and acceptor loop dynamics to control critical events leading to Dol-P-Man synthesis. The structures also rationalize the loss of dolichylphosphate mannose synthase function in dpm1-associated CDG.

Date: 2017
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DOI: 10.1038/s41467-017-00187-2

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