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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11310/20:10422296

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

13

Strana od-do

5273

Kód UT WoS článku

000585918500008

EID výsledku v databázi Scopus

2-s2.0-85092790726