Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex

Michal Lisnyansky Bar-El, Pavla Vaňková, Adva Yeheskel, Luba Simhaev, Hamutal Engel, Petr Man, Yoni Haitin () and Moshe Giladi ()
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Michal Lisnyansky Bar-El: Tel-Aviv University
Pavla Vaňková: Division BioCeV
Adva Yeheskel: Tel Aviv University
Luba Simhaev: Tel Aviv University
Hamutal Engel: Tel Aviv University
Petr Man: Division BioCeV
Yoni Haitin: Tel-Aviv University
Moshe Giladi: Tel-Aviv University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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, mutations in hcis-PT cause severe human diseases. Here, we reveal that hcis-PT exhibits a heterotetrameric assembly in solution, consisting of two catalytic dehydrodolichyl diphosphate synthase (DHDDS) and inactive Nogo-B receptor (NgBR) heterodimers. Importantly, the 2.3 Å crystal structure reveals that the tetramer assembles via the DHDDS C-termini as a dimer-of-heterodimers. Moreover, the distal C-terminus of NgBR transverses across the interface with DHDDS, directly participating in active-site formation and the functional coupling between the subunits. Finally, we explored the functional consequences of disease mutations clustered around the active-site, and in combination with molecular dynamics simulations, we propose a mechanism for hcis-PT dysfunction in retinitis pigmentosa. Together, our structure of the hcis-PT complex unveils the dolichol synthesis mechanism and its perturbation in disease.

Date: 2020
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DOI: 10.1038/s41467-020-18970-z

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