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Structural basis for long-chain isoprenoid synthesis by cis-prenyltransferases
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SYSNO ASEP 0557998 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Structural basis for long-chain isoprenoid synthesis by cis-prenyltransferases Author(s) Giladi, M. (IL)
Bar-El, M. (IL)
Vaňková, Pavla (MBU-M) ORCID
Ferofontov, A. (IL)
Melvin, E. (IL)
Alkaderi, S. (IL)
Kavan, Daniel (MBU-M) RID, ORCID
Redko, B. (IL)
Haimov, E. (IL)
Wiener, R. (IL)
Man, Petr (MBU-M) RID, ORCID
Haitin, Y. (IL)Article number eabn1171 Source Title Science Advances. - : American Association for the Advancement of Science - ISSN 2375-2548
Roč. 8, č. 20 (2022)Number of pages 14 s. Language eng - English Country US - United States Keywords undecaprenyl-pyrophosphate synthase ; length determination mechanism ; nogo-b receptor ; protein glycosylation ; exchange ; inhibitor ; insights ; mutation ; subunit ; complex Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects LM2018127 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000798164800022 EID SCOPUS 85130283475 DOI 10.1126/sciadv.abn1171 Annotation 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2023 Electronic address https://www.science.org/doi/10.1126/sciadv.abn1171
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