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Protein Science, Vol 6, Issue 9 1910-1919, Copyright © 1997 by Cold Spring Harbor Laboratory Press

ARTICLE

pH Titration studies of an SH2 domain-phosphopeptide complex: Unusual histidine and phosphate pK(a) values

A. U. SINGER and J. D. FORMAN-KAY
Department of Molecular and Medical Genetics, University of Toronto, Canada Biochemistry Research Division, Hospital for Sick Children and Department of Biochemistry, University of Toronto, Canada

Electrostatic interactions in a complex of the phospholipase C-{gamma}(1) C-terminal SH2 domain with a high-affinity binding phosphopeptide representing the sequence around Tyr 1021 of the {beta} platelet-derived growth factor receptor were studied by pK(a) determination of various titratable groups over the pH range of 5 to 8. A histidine residue that is highly conserved among SH2 domains (His {beta}D4) and the phosphotyrosine (pTyr) phosphate group show pK(a) values significantly lower than average for these residue types in proteins. The reduced pK(a) of these two groups is due to the proximity of the highly positively charged pTyr binding pocket. The unusual pK(a) of His {beta}D4 is also due to burial from solvent in a hydrogen-bonding network that appears necessary for the positioning of arginine residues involved in pTyr binding. Mutation of the analogous histidine in other SH2 domains has been shown to abrogate pTyr binding. In addition to these large shifts in pK(a) values, smaller effects were observed for the titratable groups of a glutamic acid and histidine near the C-terminus of the second helix due to its helical dipole. Finally, exchange behavior of arginine guanidinium protons with solvent as a function of pH in this SH2 domain-phosphopeptide complex confirms previous descriptions of the roles of different arginines in the structure and function of this protein.
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M. Wojciechowski, T. Grycuk, J. M. Antosiewicz, and B. Lesyng
Prediction of Secondary Ionization of the Phosphate Group in Phosphotyrosine Peptides
Biophys. J., February 1, 2003; 84(2): 750 - 756.
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