2. Academic Validation
  3. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation

Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation

  • Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. doi: 10.1073/pnas.2008381117.
Ban H Edani 1 2,  Kariona A Grabińska 1 2,  Rong Zhang 1 2,  Eon Joo Park 1 2,  Benjamin Siciliano 1 2,  Liliana Surmacz 3,  Ya Ha 4,  William C Sessa 5 2
Affiliations

Affiliations

  • 1 Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520.
  • 2 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
  • 3 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106, Warsaw, Poland.
  • 4 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; [email protected] [email protected].
  • 5 Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; [email protected] [email protected].
PMID: 32817466 DOI: 10.1073/pnas.2008381117
Abstract

Cis-prenyltransferase (cis-PTase) catalyzes the rate-limiting step in the synthesis of glycosyl carrier lipids required for protein glycosylation in the lumen of endoplasmic reticulum. Here, we report the crystal structure of the human NgBR/DHDDS complex, which represents an atomic resolution structure for any heterodimeric cis-PTase. The crystal structure sheds LIGHT on how NgBR stabilizes DHDDS through dimerization, participates in the enzyme's active site through its C-terminal -RXG- motif, and how Phospholipids markedly stimulate cis-PTase activity. Comparison of NgBR/DHDDS with homodimeric cis-PTase structures leads to a model where the elongating isoprene chain extends beyond the enzyme's active site tunnel, and an insert within the α3 helix helps to stabilize this energetically unfavorable state to enable long-chain synthesis to occur. These data provide unique insights into how heterodimeric cis-PTases have evolved from their ancestral, homodimeric forms to fulfill their function in long-chain polyprenol synthesis.

Keywords

cis-prenyltransferase; dolichol; glycosylation.

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