Proteomics

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Structural analysis of human cis-prenyltransferase

ABSTRACT: Isoprenoids are synthesized by the prenyltransferases 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, due to 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. Finally, 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.

INSTRUMENT(S): Bruker Daltonics solarix series

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Petr Man  

LAB HEAD: Petr Man

PROVIDER: PXD031707 | Pride | 2022-06-09

REPOSITORIES: Pride

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DHDDS.fasta Fasta
NBGR.fasta Fasta
PM_cisPT-crap_20210603.fasta Fasta
checksum.txt Txt
cisPT_10m_12262.d.zip Other
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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 <i>cis</i>-prenyltransferase complex (h<i>cis</i>-PT), residing at the endoplasmic reticu  ...[more]

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