Download MendeleyStructural mechanisms of allosteric regulation in the human cis-prenyltransferase complex.
Giladi, M., Kredi, S., Guardiani, C., Aviram, L., Vankova, P., Gaizinger, Y., Man, P., Giacomello, A., Haitin, Y.(2025) Nat Commun 16: 10786-10786
- PubMed: 41315348
- DOI: https://doi.org/10.1038/s41467-025-65833-6
- Primary Citation of Related Structures:
9R08, 9R0E, 9R0K - PubMed Abstract:
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 βD-βE loop, highlighting it as an allosteric hub. Functional mutagenesis scanning identified NgBR S249 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.
- Department of Physiology and Pharmacology, Gray Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel. moshegil@post.tau.ac.il.
Organizational Affiliation:
