Structural mechanisms of allosteric regulation in the human cis-prenyltransferase complex
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F25%3A00645755" target="_blank" >RIV/61388971:_____/25:00645755 - isvavai.cz</a>
Alternative codes found
RIV/86652036:_____/25:00645755
Result on the web
<a href="https://www.nature.com/articles/s41467-025-65833-6" target="_blank" >https://www.nature.com/articles/s41467-025-65833-6</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41467-025-65833-6" target="_blank" >10.1038/s41467-025-65833-6</a>
Alternative languages
Result language
angličtina
Original language name
Structural mechanisms of allosteric regulation in the human cis-prenyltransferase complex
Original language description
Human cis-prenyltransferase (hcis-PT) synthesizes long-chain isoprenoids essential for N-linked protein glycosylation. This heteromeric complex comprises the catalytic subunit DHDDS and the regulatory Nogo-B receptor (NgBR). Although NgBR dramatically enhances DHDDS activity, the molecular basis for this allosteric regulation remains unclear. Here, we combined crystallography, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics simulations, and network analysis to uncover the structural dynamics and communication pathways within hcis-PT. By solving the apo structure of hcis-PT, we reveal only a localized flexibility at the active site and the NgBR C-terminus. However, HDX-MS demonstrated widespread substrate-induced stabilization, particularly at the NgBR beta D-beta E loop, highlighting it as an allosteric hub. Functional mutagenesis scanning identified NgBRS249 as critical for enzymatic activity, independent of structural perturbations. Network analysis of MD simulations pinpointed this residue as a central node in inter-subunit communication, with perturbations disrupting downstream allosteric pathways, altering enzymatic activity. Our findings reveal a dynamic regulatory network centered at the inter-subunit interface, wherein specific NgBR residues modulate DHDDS activity through allosteric signaling. This work elucidates a conserved mechanism of subunit coordination in long-chain cis-prenyltransferases and suggests avenues for therapeutic targeting of hcis-PT-related disorders.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10606 - Microbiology
Result continuities
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
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Nature Communications
ISSN
2041-1723
e-ISSN
2041-1723
Volume of the periodical
16
Issue of the periodical within the volume
November 28
Country of publishing house
GB - UNITED KINGDOM
Number of pages
12
Pages from-to
10786
UT code for WoS article
001627854600031
EID of the result in the Scopus database
2-s2.0-105023334766