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

Nat Commun. 2020 Oct 19;11(1):5273. doi: 10.1038/s41467-020-18970-z.


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 Å 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / chemistry*
  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism
  • Amino Acid Motifs
  • Catalytic Domain
  • Dimerization
  • Humans
  • Mutation
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Retinitis Pigmentosa / enzymology
  • Retinitis Pigmentosa / genetics*
  • Transferases / chemistry*
  • Transferases / genetics*
  • Transferases / metabolism


  • NUS1 protein, human
  • Receptors, Cell Surface
  • Transferases
  • Alkyl and Aryl Transferases
  • cis-prenyl transferase
  • dehydrodolichyl diphosphate synthetase