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PDBsum entry 3cy6
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Unknown function
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PDB id
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3cy6
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References listed in PDB file
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Key reference
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Title
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Cysteine pka depression by a protonated glutamic acid in human dj-1.
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Authors
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A.C.Witt,
M.Lakshminarasimhan,
B.C.Remington,
S.Hasim,
E.Pozharski,
M.A.Wilson.
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Ref.
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Biochemistry, 2008,
47,
7430-7440.
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PubMed id
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Abstract
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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.
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