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#GPI anchor

3 public questions tagged with this topic.

Plasma Membrane Proteins

Which of the following proteins uses a GPI anchor to attach to the membrane?

Classification of lipid-anchored proteins includes GPI anchor addition in endoplasmic reticulum lumen via multi-step pathway conserved across eukaryotes. GPI precursor synthesis starts on cytoplasmic face adding N-acetylglucosamine to phosphatidylinositol by PIG-A, deacetylation by PIG-L, flipping to luminal side by flippase, addition of three mannose residues from dolichol-phosphate-mannose by PIG-M PIG-V PIG-B, addition of phosphoethanolamine by PIG-O PIG-F, final transfer en bloc to C-terminal GPI signal peptide cleavage site containing omega site small residues by GPI transamidase comprising PIG-K catalytic cysteine protease forming amide bond between protein carboxyl and phosphoethanolamine linked to terminal mannose glycan mannose core attached via glucosamine to inositol diacylglycerol embedding in outer leaflet. Proteins remain tethered high lateral mobility localized lipid rafts cleavable by phospholipase C or D releasing soluble forms. Examples hydrolytic enzymes alkaline phosphatase ecto-5 nucleotidase, adhesion molecules Thy-1 CD90, prion PrPc, regulators CD55 CD59. Multipass proteins aquaporin six helices Band 3 fourteen helices GPCR seven helices cross bilayer via peptide helices not lipid tether, distinguishing GPI-linked class.

Ref: Mayor and Riezman, Sorting GPI-Anchored Proteins, Nature Reviews Mol Cell Biol 2004.

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Plasma Membrane Proteins

Which type of membrane protein is covalently linked to a lipid moiety, anchoring it to the membrane?

Lipid linkage expands repertoire of membrane association beyond hydrophobic transmembrane spans enabling reversible targeting. Four major classes documented: N-myristoylation fourteen-carbon saturated fatty acid amide linked to N-terminal glycine after methionine removal catalyzed by N-myristoyltransferase cotranslationally; S-palmitoylation sixteen-carbon palmitate thioester linked to cysteine catalyzed by DHHC palmitoyl acyltransferases reversible by thioesterases controlling trafficking; prenylation fifteen-carbon farnesyl or twenty-carbon geranylgeranyl thioether linked to C-terminal CAAX cysteine by farnesyltransferase and geranylgeranyltransferases followed by proteolysis by RCE1 and carboxyl methylation by ICMT; GPI anchoring where preassembled glycolipid comprising ethanolamine phosphate oligosaccharide glucosamine mannose inositol diacylglycerol attached to C-terminal cleavage site via transamidase embedding in outer leaflet. These moieties embed in one leaflet providing raft affinity, polarized sorting and assembly of signalosomes for Ras Rab Src G-alpha and alkaline phosphatase families distinct from multipass integral proteins like channels that cross bilayer via peptide helices. Each modification uses distinct metabolite donors myristoyl-CoA palmitoyl-CoA farnesyl diphosphate and preassembled GPI precursor dictating substrate specificity and cellular localization.

Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 10, Lipid-Anchored Membrane Proteins.

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Lipid Link Protein

What type of lipid linkage does CD59 have?

CD59 protectin MIRL MAC-inhibitory protein exemplifies complement regulation through GPI anchoring. Gene located chromosome eleven encodes one hundred twenty eight amino acids including twenty six residue C-terminal GPI signal peptide removed in endoplasmic reticulum. Preassembled GPI precursor synthesized via stepwise addition of N-acetylglucosamine to phosphatidylinositol, deacetylation, addition of three mannose residues via PIG enzymes, and phosphoethanolamine addition is transferred en bloc by GPI transamidase containing PIG-K catalytic subunit forming amide bond between protein and phosphoethanolamine linked to terminal mannose, core glycan containing glucosamine connecting to inositol phospholipid diacylglycerol embedded in outer leaflet. Resulting anchor confers partition into lipid rafts and rapid lateral diffusion to sites of complement activation where CD59 binds C8 alpha and C9 first transmembrane region blocking polymerization of membrane attack complex pore. Bacterial PI-PLC cleavage releases CD59. Paroxysmal nocturnal hemoglobinuria caused by somatic PIGA mutation disrupting GPI synthesis eliminates CD59 and CD55 causing hemolysis detected by flow cytometry FLAER staining.

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Section: GPI-Anchored Proteins – CD59 and Complement Regulation.

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