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Da Silva et al. develop the first mouse model of DHDDS-related progressive epileptic encephalopathy, showing that a disease-causing Dhdds variant produces

A team at the Centre de recherche Azrieli du CHU Sainte-Justine has reached a major milestone in understanding a rare and severe form of genetic encephalopathy associated with the DHDDS gene.

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...

N-glycosylation, driven by the cis-prenyltransferase (cis-PT) complex, a NUS1 and DHDDS heterotetramer, is vital for proteome integrity. Despite being linked to severe congenital disorders of glycosyl...

A team at the Centre de recherche Azrieli du CHU Sainte-Justine has reached a major milestone in understanding a rare and severe form of genetic encephalopathy associated with the DHDDS gene. By developing the first mouse model that faithfully reproduces one of the human forms of the disease, researcher Alexey Pshezhetsky, a professor in the Department of Pediatrics, and Dr. Elsa Rossignol, a professor in the Department of Neuroscience, both at UdeM, provide the scientific community with an unprecedented tool to investigate the biological mechanisms underlying this neurodevelopmental disorder and accelerate the development of new therapeutic strategies.

A form of vitamin B3 known as nicotinamide mononucleotide was found to slow disease progression in patients with a rare mutation in the DHDDS gene

A form of vitamin B3 known as nicotinamide mononucleotide was found to slow disease progression in patients with a rare mutation in the DHDDS gene

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 novel avenues for therapeutic targeting of hcis-PT-related disorders.

Two of three siblings from London carry a mutation of the DHDDS gene