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bioRxiv · 10.1101/2020.06.03.132209

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

Edani, B. H.·Grabinsko, K. A.·Zhang, R.·Park, E. J.·Siciliano, B.·Surmacz, L.·Ha, Y.·Sessa, B.
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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 the first atomic resolution structure for any heterodimeric cis-PTase. The crystal structure sheds light on how NgBR stabilizes DHDDS through dimerization, participates in the enzymes 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 enzymes active site tunnel, and an insert within the 3 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.

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Edani, B. H., Grabinsko, K. A., Zhang, R., Park, E. J., Siciliano, B., Surmacz, L., Ha, Y., Sessa, B.. 2020-06-03. Structural elucidation of the heterodimeric cis-prenyltransferase NgBR/DHDDS complex reveals novel insights in regulation of protein glycosylation. https://doi.org/10.1101/2020.06.03.132209

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