GLYCOLIPID PROTEIN ANCHORS IN PNH AND THY-1 MUTANTS

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Plasma membrane proteins anchored via a glycophospholipid are of critical importance for a number of metabolic and homeostatic functions. Moreover, their modulation may result in the ability of cells to escape immune recognition. The present proposal is concerned with three such proteins: decay accelerating factor (DAF), acetylcholinesterase, and Thy-1. The proposal is highly inter-disciplinary--both from a conceptual and from a technical point of view--and exploits chemical, cell biological, biochemical, molecular biological and immunological approaches. The extensive investigation of the structure of the anchor of acetylcholinesterase makes use of human red cells; the studies of Thy-1 focus on a family of five mouse lymphoma mutants which synthesize Thy-1 but fail to express it on the cell surface, apparently due to an inability to synthesize its anchor; the studies of DAF concern fluids, tissues and cultured cells of control individuals and of individuals suffering from paroxysmal nocturnal hemoglobinuria (PNH). In this disease, cell surface DAF (and acetylcholinesterase) are grossly deficient, although precursor species of DAF are synthesized. The underlying in PNH may, therefore, be related to those of the Thy-1 negative mutants. The unifying theme of the proposed research is the structure, biosynthesis and function(s) of glycophospholipid anchors.