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

ML. Bar-El, P. Vaňková, A. Yeheskel, L. Simhaev, H. Engel, P. Man, Y. Haitin, M. Giladi,

. 2020 ; 11 (1) : 5273. [pub] 20201019

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20027724

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.

Citace poskytuje Crossref.org

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$a The human cis-prenyltransferase (hcis-PT) is an enzymatic complex essential for protein N-glycosylation. Synthesizing the precursor of the glycosyl carrier dolichol-phosphate, mutations in hcis-PT cause severe human diseases. Here, we reveal that hcis-PT exhibits a heterotetrameric assembly in solution, consisting of two catalytic dehydrodolichyl diphosphate synthase (DHDDS) and inactive Nogo-B receptor (NgBR) heterodimers. Importantly, the 2.3 Å crystal structure reveals that the tetramer assembles via the DHDDS C-termini as a dimer-of-heterodimers. Moreover, the distal C-terminus of NgBR transverses across the interface with DHDDS, directly participating in active-site formation and the functional coupling between the subunits. Finally, we explored the functional consequences of disease mutations clustered around the active-site, and in combination with molecular dynamics simulations, we propose a mechanism for hcis-PT dysfunction in retinitis pigmentosa. Together, our structure of the hcis-PT complex unveils the dolichol synthesis mechanism and its perturbation in disease.
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$a Vaňková, Pavla $u Institute of Microbiology of the Czech Academy of Sciences, Division BioCeV, Prumyslova, 595, 252 50, Vestec, Czech Republic. Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43, Prague 2, Czech Republic.
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$a Yeheskel, Adva $u Blavatnik Center for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel.
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$a Haitin, Yoni $u Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel. yhaitin@tauex.tau.ac.il. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel. yhaitin@tauex.tau.ac.il.
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$a Giladi, Moshe $u Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel. moshegil@post.tau.ac.il. Tel Aviv Sourasky Medical Center, Tel Aviv, 6423906, Israel. moshegil@post.tau.ac.il.
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