6Z1N

Structure of the human heterotetrameric cis-prenyltransferase complex

Summary for 6Z1N

• Entry DOI: 10.2210/pdb6z1n/pdb
• Descriptor: Dehydrodolichyl diphosphate synthase complex subunit DHDDS, Dehydrodolichyl diphosphate synthase complex subunit NUS1, FARNESYL DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: dolichol, cis-prenyltransferase, ngbr, dhdds, nogo-b receptor, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 63915.16

Authors

Lisnyansky Bar-El, M.,Haitin, Y.,Giladi, M. (deposition date: 2020-05-14, release date: 2020-10-21, Last modification date: 2024-01-24)

Primary citation

Bar-El, M.L.,Vankova, P.,Yeheskel, A.,Simhaev, L.,Engel, H.,Man, P.,Haitin, Y.,Giladi, M.
Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex.
Nat Commun, 11:5273-5273, 2020

PubMed Abstract: 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.

PubMed: 33077723
DOI: 10.1038/s41467-020-18970-z

Experimental method

X-RAY DIFFRACTION (2.3 Å)