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Structure of the human heterotetrameric cis-prenyltransferase complex

View ORCID ProfileMichal Lisnyansky Bar-El, Pavla Vankova, View ORCID ProfilePetr Man, View ORCID ProfileYoni Haitin, View ORCID ProfileMoshe Giladi
doi: https://doi.org/10.1101/2020.06.02.095570
Michal Lisnyansky Bar-El
1Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel
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  • ORCID record for Michal Lisnyansky Bar-El
Pavla Vankova
2Institute of Microbiology of the Czech Academy of Sciences, Division BioCeV, Prumyslova 595, 252 50 Vestec, Czech Republic
3Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague 2, Czech Republic
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Petr Man
2Institute of Microbiology of the Czech Academy of Sciences, Division BioCeV, Prumyslova 595, 252 50 Vestec, Czech Republic
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Yoni Haitin
1Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel
4Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel
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  • For correspondence: yhaitin@tauex.tau.ac.il moshegil@post.tau.ac.il
Moshe Giladi
1Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel
5Tel Aviv Sourasky Medical Center, Tel Aviv, 6423906, Israel
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  • For correspondence: yhaitin@tauex.tau.ac.il moshegil@post.tau.ac.il
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Abstract

The human cis-prenyltransferase (hcis-PT) is an enzymatic complex essential for protein N-glycosylation. Synthesizing the precursor of the glycosyl carrier dolichol-phosphate, we reveal here that hcis-PT exhibits a novel heterotetrameric assembly in solution, composed of two catalytic dehydrodolichyl diphosphate synthase (DHDDS) and two inactive Nogo-B receptor (NgBR) subunits. The 2.3 Å crystal structure of the complex exposes a dimer-of-heterodimers arrangement, with DHDDS C-termini serving as homotypic assembly domains. Furthermore, the structure elucidates the molecular details associated with substrate binding, catalysis, and product length determination. Importantly, the distal C-terminus of NgBR transverses across the heterodimeric interface, directly participating in substrate binding and underlying the allosteric communication between the subunits. Finally, mapping disease-associated hcis-PT mutations involved in blindness, neurological and glycosylation disorders onto the structure reveals their clustering around the active site. Together, our structure of the hcis-PT complex unveils the dolichol synthesis mechanism and its perturbation in disease.

Competing Interest Statement

The authors have declared no competing interest.

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Posted June 02, 2020.
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Structure of the human heterotetrameric cis-prenyltransferase complex
Michal Lisnyansky Bar-El, Pavla Vankova, Petr Man, Yoni Haitin, Moshe Giladi
bioRxiv 2020.06.02.095570; doi: https://doi.org/10.1101/2020.06.02.095570
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Structure of the human heterotetrameric cis-prenyltransferase complex
Michal Lisnyansky Bar-El, Pavla Vankova, Petr Man, Yoni Haitin, Moshe Giladi
bioRxiv 2020.06.02.095570; doi: https://doi.org/10.1101/2020.06.02.095570

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