7pb0

Structure of the human heterotetrameric cis-prenyltransferase complex in complex with magnesium, GGsPP and IsPPStructure of the human heterotetrameric cis-prenyltransferase complex in complex with magnesium, GGsPP and IsPP

Structural highlights

7pb0 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 2.301Å
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

Isoprenoids are synthesized by the prenyltransferase superfamily, which is subdivided according to the product stereoisomerism and length. In short- and medium-chain isoprenoids, product length correlates with active site volume. However, enzymes synthesizing long-chain products and rubber synthases fail to conform to this paradigm, because of an unexpectedly small active site. Here, we focused on the human cis-prenyltransferase complex (hcis-PT), residing at the endoplasmic reticulum membrane and playing a crucial role in protein glycosylation. Crystallographic investigation of hcis-PT along the reaction cycle revealed an outlet for the elongating product. Hydrogen-deuterium exchange mass spectrometry analysis showed that the hydrophobic active site core is flanked by dynamic regions consistent with separate inlet and outlet orifices. Last, using a fluorescence substrate analog, we show that product elongation and membrane association are closely correlated. Together, our results support direct membrane insertion of the elongating isoprenoid during catalysis, uncoupling active site volume from product length.

Structural basis for long-chain isoprenoid synthesis by cis-prenyltransferases.,Giladi M, Lisnyansky Bar-El M, Vankova P, Ferofontov A, Melvin E, Alkaderi S, Kavan D, Redko B, Haimov E, Wiener R, Man P, Haitin Y Sci Adv. 2022 May 20;8(20):eabn1171. doi: 10.1126/sciadv.abn1171. Epub 2022 May , 18. PMID:35584224^[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
↑ Giladi M, Lisnyansky Bar-El M, Vaňková P, Ferofontov A, Melvin E, Alkaderi S, Kavan D, Redko B, Haimov E, Wiener R, Man P, Haitin Y. Structural basis for long-chain isoprenoid synthesis by cis-prenyltransferases. Sci Adv. 2022 May 20;8(20):eabn1171. PMID:35584224 doi:10.1126/sciadv.abn1171

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] Giladi M, Lisnyansky Bar-El M, Vaňková P, Ferofontov A, Melvin E, Alkaderi S, Kavan D, Redko B, Haimov E, Wiener R, Man P, Haitin Y. Structural basis for long-chain isoprenoid synthesis by cis-prenyltransferases. Sci Adv. 2022 May 20;8(20):eabn1171. PMID:35584224 doi:10.1126/sciadv.abn1171

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