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6z1n

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Structure of the human heterotetrameric cis-prenyltransferase complex

Structural highlights

6z1n is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DHDDS_HUMAN Non-specific early-onset epileptic encephalopathy;Retinitis pigmentosa. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry.

Function

DHDDS_HUMAN With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER) (PubMed:25066056, PubMed:28842490, PubMed:32817466). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length (PubMed:32817466). Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol (PubMed:21572394).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

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 A 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.

Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex.,Bar-El ML, Vankova P, Yeheskel A, Simhaev L, Engel H, Man P, Haitin Y, Giladi M Nat Commun. 2020 Oct 19;11(1):5273. doi: 10.1038/s41467-020-18970-z. PMID:33077723^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Harrison KD, Park EJ, Gao N, Kuo A, Rush JS, Waechter CJ, Lehrman MA, Sessa WC. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 2011 May 13;30(12):2490-500. PMID:21572394 doi:10.1038/emboj.2011.147
↑ Park EJ, Grabinska KA, Guan Z, Stranecky V, Hartmannova H, Hodanova K, Baresova V, Sovova J, Jozsef L, Ondruskova N, Hansikova H, Honzik T, Zeman J, Hulkova H, Wen R, Kmoch S, Sessa WC. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 2014 Sep 2;20(3):448-57. doi: 10.1016/j.cmet.2014.06.016. Epub 2014, Jul 24. PMID:25066056 doi:http://dx.doi.org/10.1016/j.cmet.2014.06.016
↑ Grabińska KA, Edani BH, Park EJ, Kraehling JR, Sessa WC. A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity. J Biol Chem. 2017 Oct 20;292(42):17351-17361. PMID:28842490 doi:10.1074/jbc.M117.806034
↑ Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. PMID:32817466 doi:10.1073/pnas.2008381117
↑ Bar-El ML, Vaňková 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. 2020 Oct 19;11(1):5273. PMID:33077723 doi:10.1038/s41467-020-18970-z