The covalent modification of eukaryotic proteins with lipid.

Abstract

surprisingly large number of proteins in eukaryotic ceils are now known to contain covalently bound lipid. Several cell surface proteins, the Thy-1 glycoprotein (27, 55), acetylcholinesterase (14), alkaline phosphatase (28), and the variant surface glycoprotein of trypanosomes (13), among others, are anchored to the outer cell surface by a complex, glycosylated phospholipid (Table I; Fig. 1). A second group of proteins, which are found within the cell, contain the 14 carbon saturated fatty acid myristic acid at their amino-termini (Table I; Fig. 1). Included in this class is the product of the c-src proto-oncogene, p60 ~-sr~ (5); the catalytic subunit of the cAMP-dependent protein kinase (9); the protein phosphatase calcineurin (1); a gag internal structural protein of mammalian retroviruses (18); and a number of viral transforming proteins (48). Finally, the surface glycoproteins of several enveloped viruses (45-47), the HLA glycoprotein (24, 50), the transforming protein of Harvey sarcoma virus, p21 r~ (6, 11, 50), and the transferrin receptor (36) are part of a diverse third class of proteins that contain the 16 carbon saturated fatty acid palmitic acid linked to cysteine (Table I; Fig. 1). The modification of protein with lipid is not simply a biochemical curiosity. Lipid is, in several cases, clearly required for the binding of proteins to cellular membranes. Treatment ofceUs with phospholipase C, an enzyme that can cleave the lipid from acetylcholinesterase, alkaline phosphatase, and the Thy-1 glycoprotein, releases a significant fraction of each of these proteins (14, 27, 28). Additionally, point mutations that prevent myristylation of p60 ~ and Pr65sa~ and palmitylation of p21 ~ render these proteins unable to bind to membranes (8, 22, 40, 57). It has become clear therefore that the signals and sequences necessary for a protein to bind to a membrane need not be present in the primary structure of the protein, but can instead be acquired through co-translational or posttranslational modification. Myristylation, palmitylation, and the addition of the complex glyco-phospholipid occur by remarkably different mechanisms.