Does the tail wag the dog? How the structure of a protein’s “tail” affects its function
Many proteins are attached to cell membranes by a glyco-lipid “tail” known as a glycosylphosphatidylinositol (GPI) anchor. It is becoming apparent that differences in the composition of these GPIs have profound influences upon protein structure, trafficking and function. Our recent study examined the effects of GPI structure upon the cellular prion protein (PrPC). This protein is of interest as it can be converted into an alternatively folded, disease-associated isoform (PrPSc) commonly called a prion. Accumulations of PrPSc within the brain are associated with neurodegeneration and the clinical symptoms of prion diseases such as scrapie in sheep and Creutzfeldt-Jakob disease in humans. Our recent paper examined the effects of sialic acid, a rare modification of GPIs, upon the properties of PrPC.
Our study reported 3 major observations;-
1) Desialylated PrPC is not converted to PrPSc.
2) Desialylated PrPC inhibits the conversion of PrPC to PrPSc.
3) Desialylated PrPC behaves differently from PrPC with regards to its effects on membrane composition and cell signalling.
The obvious question; why do the effects of PrPC and desialylated PrPC differ so greatly? was explored. The first clue was the observation that PrPC and desialylated PrPC were targeted to different domains within the cell membrane. The membrane surrounding GPI-anchored proteins is composed of specific phospholipids, glycolipids and cholesterol that constitute a “raft”. The composition of this raft is dependent upon interactions between the glycans on the GPI and membrane lipids. A change in the GPI, such as the loss of sialic acid, affects the composition of the surrounding membrane raft and has consequences for protein trafficking and function. Significantly higher concentrations of gangliosides and cholesterol associated with desialylated PrPC compared with PrPC and desialylated PrPC and PrPC trafficked differently within neurons.
PrPSc is thought to bind to PrPC and convert it into PrPSc in a process that occurs within membrane rafts. The composition and function of these rafts is dynamic and controlled by an “induced fit” model. Since the composition of rafts is affected by the structure of GPIs then the raft surrounding a complex between PrPSc and PrPC would be expected to differ from the raft surrounding PrPSc and desialylated PrPC. We hypothesised that the binding of desialylated PrPC to PrPSc changed the composition of local rafts so that they are unfavourable for the conversion of PrPC to PrPSc. The clustering of GPIs containing sialic acid activated cytoplasmic phospholipase A2 (cPLA2) an enzyme that promotes PrPSc formation. In the presence of desialylated PrPC, activation of cPLA2 is reduced as it dissociates from PrPSc-containing rafts. Thus, the binding of desialylated PrPC to PrPSc affects the composition of the underlying raft so that it no longer captures and activates cPLA2.
In conclusion we show that sialic acid contained within the GPI “tail” affects the properties of PrPC, altering the surrounding raft, the trafficking of PrPC and PrPC-induced cell signalling. Critically the presence of desialylated PrPC reduced the activation of cPLA2 and PrPSc formation. We propose that sialic acid on the GPI attached to PrPC affects the membrane targeting and cell signalling that is conducive to its conversion to PrPSc. Consequently, therapeutics that block the incorporation of sialic acid into GPI anchors could prove useful in the treatment of prion diseases.
Publication
Sialic Acid on the Glycosylphosphatidylinositol Anchor Regulates PrP-mediated Cell Signaling and Prion Formation.
Bate C, Nolan W, Williams A.
J Biol Chem. 2016 Jan 1
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