In:
Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-10-19)
Abstract:
The human cis -prenyltransferase (h cis -PT) is an enzymatic complex essential for protein N-glycosylation. Synthesizing the precursor of the glycosyl carrier dolichol-phosphate, mutations in h cis -PT cause severe human diseases. Here, we reveal that h cis -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 h cis -PT dysfunction in retinitis pigmentosa. Together, our structure of the h cis -PT complex unveils the dolichol synthesis mechanism and its perturbation in disease.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-020-18970-z
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2553671-0
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