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Role of Tyr84 in controlling the reactivity of Cys34 of human albumin

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Alan J Stewart, Claudia Blindauer, Stephen Berezenko, Darrell Sleep, David Tooth, Peter J Sadler

School/Research organisations


Cys34 in domain I of the three-domain serum protein albumin is the binding
site for a wide variety of biologically and clinically important small
molecules, provides antioxidant activity, and constitutes the largest portion
of free thiol in blood. Analysis of X-ray structures of albumin reveals that
the loop containing Tyr84 occurs in multiple conformations. In structures
where the loop is well defined, there appears to be an H-bond between the
OH of Tyr84 and the sulfur of Cys34. We show that the reaction of 5,5'-dithiobis(
2-nitrobenzoic acid) (DTNB) with Tyr84Phe mutant albumin is
approximately four times faster than with the wild-type protein between
pH 6 and pH 8. In contrast, the His39Leu mutant reacts with DTNB more
slowly than the wild-type protein at pH < 8, but at a similar rate at pH 8.
Above pH 8 there is a dramatic increase in reactivity for the Tyr84Phe
mutant. We also report 1H NMR studies of disulfide interchange reactions
with cysteine. The tethering of the two loops containing Tyr84 and
Cys34 not only appears to control the redox potential and accessibility of
Cys34, but also triggers the transmission of information about the state
of Cys34 throughout domain I, and to the domainI ⁄ II interface.


Original languageEnglish
Pages (from-to)353-362
Number of pages10
JournalFEBS Journal
Issue number2
Early online date16 Dec 2004
Publication statusPublished - 21 Dec 2004

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