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Cysteine pKa depression by a protonated glutamic acid in human DJ-1.

Witt AC, Lakshminarasimhan M, Remington BC, Hasim S, Pozharski E, Wilson MA
Biochemistry 47 7430-40 (2008)
Related entries: 2or3, 3cy6, 3cz9, 3cza

Cited: 69 times
EuropePMC logo PMID: 18570440

Abstract

Human DJ-1, a disease-associated protein that protects cells from oxidative stress, contains an oxidation-sensitive cysteine (C106) that is essential for its cytoprotective activity. The origin of C106 reactivity is obscure, due in part to the absence of an experimentally determined p K a value for this residue. We have used atomic-resolution X-ray crystallography and UV spectroscopy to show that C106 has a depressed p K a of 5.4 +/- 0.1 and that the C106 thiolate accepts a hydrogen bond from a protonated glutamic acid side chain (E18). X-ray crystal structures and cysteine p K a analysis of several site-directed substitutions at residue 18 demonstrate that the protonated carboxylic acid side chain of E18 is required for the maximal stabilization of the C106 thiolate. A nearby arginine residue (R48) participates in a guanidinium stacking interaction with R28 from the other monomer in the DJ-1 dimer and elevates the p K a of C106 by binding an anion that electrostatically suppresses thiol ionization. Our results show that the ionizable residues (E18, R48, and R28) surrounding C106 affect its p K a in a way that is contrary to expectations based on the typical ionization behavior of glutamic acid and arginine. Lastly, a search of the Protein Data Bank (PDB) produces several candidate hydrogen-bonded aspartic/glutamic acid-cysteine interactions, which we propose are particularly common in the DJ-1 superfamily.

Articles - 3cyf mentioned but not cited (1)

  1. Cysteine pKa depression by a protonated glutamic acid in human DJ-1. Witt AC, Lakshminarasimhan M, Remington BC, Hasim S, Pozharski E, Wilson MA. Biochemistry 47 7430-7440 (2008)


Reviews citing this publication (16)

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