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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F20%3A00535845" target="_blank" >RIV/61388971:_____/20:00535845 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/20:10422296

Result on the web

<a href="https://www.nature.com/articles/s41467-020-18970-z" target="_blank" >https://www.nature.com/articles/s41467-020-18970-z</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-020-18970-z" target="_blank" >10.1038/s41467-020-18970-z</a>

Result language

angličtina

Original language name

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

Original language description

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 angstrom 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. The human cis-prenyltransferase (hcis-PT) complex synthesizes the precursor of the glycosyl carrier dolichol-phosphate and as such it is essential for protein N-glycosylation. The crystal structure of the complex reveals unusual tetrameric architecture and provides insights into dolichol synthesis mechanism and functional consequences of disease-associated hcis-PT mutations.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Communications

ISSN

2041-1723

e-ISSN

—

Volume of the periodical

11

Issue of the periodical within the volume

1

Country of publishing house

DE - GERMANY

Number of pages

13

Pages from-to

5273

UT code for WoS article

000585918500008

EID of the result in the Scopus database

2-s2.0-85092790726