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

DOI: 10.1038/s41467-020-18970-z DOI Help

Authors: Michal Lisnyansky Bar-el (Tel Aviv University) , Pavla Vaňková (Institute of Microbiology of the Czech Academy of Sciences; Charles University) , Adva Yeheskel (Tel Aviv University) , Luba Simhaev (Tel Aviv University) , Hamutal Engel (Tel Aviv University) , Petr Man (Institute of Microbiology of the Czech Academy of Sciences) , Yoni Haitin (Tel Aviv University) , Moshe Giladi (Tel-Aviv University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: October 2020

Open Access Open Access

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.

Journal Keywords: Enzymes; Mitochondria; Transferases

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

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s41467-020-18970-z.pdf