7pb0
Structure of the human heterotetrameric cis-prenyltransferase complex in complex with magnesium, GGsPP and IsPP
Structural highlights
DiseaseDHDDS_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. FunctionDHDDS_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 PubMedIsoprenoids 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
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