Are phosphorylated tyrosine residues of certain receptors involved in inducing transitory covalent protein cross-linking?
Following ligand binding a number of cell-surface receptors become phosphorylated at tyrosine residues of their cytosolic domains. These phosphorylations are associated with initiation of a signalling programme involving a sequence of tyrosine-phosphorylated protein-protein interactions. In the recognition process between phosphorylated proteins, electrostatic interactions between negatively charged phosphorylated tyrosines, serine and threonine residues and positively charged lysines play an important role as well as hydrophobic and H-bonding reactions. We suggest in this paper that the fairly high-energy phosphate bond of certain protein phosphorylated tyrosines are possibly involved in inducing transitory protein cross-linking reactions. Through a process involving transfer of an activated phosphate of phosphorylated tyrosine to a side-chain carboxyl group of the receptor or next protein of the signalling sequence, an acyl phosphate is formed. This then acylates a hydroxyl group on a serine, threonine or tyrosine residue of the protein not carrying the carboxyl phosphate to give an ester linkage, thus cross-linking the two proteins of the signalling pathway. The covalent ester linkage is labile to hydrolysis and depending on the protein-protein molecular environment it might have a finite half-life. On hydrolysis, the transitory covalent linkage is broken with separation of the proteins. It is suggested therefore that formation of a protein-protein ester linkage introduces a type of timing device into the system. Breakdown of the original protein-phosphorylated tyrosine in this case therefore does not involve a phosphatase enzyme.
Hawtrey
A O
AO
Department of Pharmacology, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa.
Van Jaarsveld
P P
PP
Ariatti
M
M
D000818:Animals; D008956:Models, Chemical; D008961:Models, Structural; D010750:Phosphoproteins / Q000378:metabolism*; D010768:Phosphoserine; D010769:Phosphothreonine; D019000:Phosphotyrosine; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D055672:Static Electricity
D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine