Dataset Information

Phenylmethanesulphonyl fluoride inhibits GPI anchor biosynthesis in the African trypanosome.

ABSTRACT: A wide variety of eukaryotic membrane proteins are anchored to the outside of cells by covalent linkage to glycosyl phosphatidylinositol (GPI). One of the best characterized examples is the variant surface glycoprotein (VSG) of the protozoan parasite, Trypanosoma brucei. The structure of the GPI precursor is ethanolamine-PO4-Man alpha 1-2Man alpha 1-6Man alpha 1-4GlcNH2-PI; the phosphoethanolamine moiety forms an amide linkage to the VSG polypeptide alpha-COOH group during its attachment to protein. Here we report that the serine esterase inhibitor, phenylmethanesulphonyl fluoride (PMSF), inhibits phosphoethanolamine incorporation into the GPI precursor resulting in the accumulation of a Man3GlcNH2-PI intermediate. PMSF exerts this effect both in living trypanosomes and in a trypanosome-derived cell-free system. This is the first report of an inhibitor which affects GPI biosynthesis but not N-glycosylation. A model of the mechanism of phosphoethanolamine incorporation into the GPI precursor, based on the known properties of PMSF, is presented.

SUBMITTER: Masterson WJ

PROVIDER: S-EPMC452885 | biostudies-literature | 1991 Aug

REPOSITORIES: biostudies-literature

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Phenylmethanesulphonyl fluoride inhibits GPI anchor biosynthesis in the African trypanosome.

Masterson W J WJ Ferguson M A MA

The EMBO journal 19910801 8

A wide variety of eukaryotic membrane proteins are anchored to the outside of cells by covalent linkage to glycosyl phosphatidylinositol (GPI). One of the best characterized examples is the variant surface glycoprotein (VSG) of the protozoan parasite, Trypanosoma brucei. The structure of the GPI precursor is ethanolamine-PO4-Man alpha 1-2Man alpha 1-6Man alpha 1-4GlcNH2-PI; the phosphoethanolamine moiety forms an amide linkage to the VSG polypeptide alpha-COOH group during its attachment to prot ...[more]

PMID: 1829674

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Project description:BackgroundDefects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage).ResultsWe addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities.ConclusionsIGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs.

Dataset Information

Phenylmethanesulphonyl fluoride inhibits GPI anchor biosynthesis in the African trypanosome.

Publications

Phenylmethanesulphonyl fluoride inhibits GPI anchor biosynthesis in the African trypanosome.

Similar Datasets

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