CONSERVED PHOSPHORYLATION OF SERINES IN THE SER-X-GLU SER(P) SEQUENCES OF THE VITAMIN-K-DEPENDENT MATRIX GLA PROTEIN FROM SHARK, LAMB, RAT,COW, AND HUMAN/

The present studies demonstrate that matrix Gla protein (MGP), a 10-kD a vitamin K-dependent protein, is phosphorylated at 3 serine residues near its N-terminus. Phosphoserine was identified at residues 3, 6, an d 9 of bovine, human, rat, and lamb MGP by N-tenninal protein sequenci ng. Ah 3 modified serines are in tandemly repeated Ser-X-Glu sequences ; Two of the serines phosphorylated in shark MGP, residues 2 and 5, al so have glutamate residues in the n + 2 position in tandemly repeated Ser-X-Glu sequences, whereas the third, shark residue 3, would acquire an acidic phosphoserine in the n + 2 position upon phosphorylation of serine 5. The recognition motif found for MGP phosphorylation, Ser-X- Glu/Ser(P), has been seen previously in milk caseins, salivary protein s, and a number of regulatory peptides. A review of the Literature has revealed an intriguing dichotomy in the extent of serine phosphorylat ion among secreted proteins that are phosphorylated at Ser-X-Glu/Ser(P ) sequences. Those phosphoproteins secreted into milk or saliva are fu lly phosphorylated at each target serine, whereas phosphoproteins secr eted into the extracellular environment of cells are partially phospho rylated at target serine residues, as we show here for MGP and others have shown for regulatory peptides and the insulin-like growth factor binding protein 1. We propose that the extent of serine phosphorylatio n regulates the activity of proteins secreted into the extracellular e nvironment of cells, and that partial phosphorylation can therefore be explained by the need to ensure that the phosphoprotein be poised to gain or lose activity with regulated changes in phosphorylation status .