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Physiol. Genomics (October 26, 2004). doi:10.1152/physiolgenomics.00204.2004
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Submitted on September 7, 2004
Accepted on October 25, 2004

Altered Specificity of Hint-W123Q Supports a Role for Hint Inhibition by Asw in Avian Sex Determination

Kristen P Parks1, Heather Seidle1, Nathan Wright1, Jeffrey B Sperry2, Pawel Bieganowski1, Konrad Howitz3, Dennis L Wright2, and Charles Brenner1*

1 Departments of Genetics and Biochemistry and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA
2 Department of Chemistry, Dartmouth College, Hanover, NH, USA
3 Biomol, Inc., Plymouth Meeting, PA, USA

* To whom correspondence should be addressed. E-mail: charles.brenner{at}dartmouth.edu.

Hint is a universally conserved, dimeric AMP-lysine hydrolase encoded on the avian Z chromosome. Tandemly repeated on the female-specific W chromosome, Asw is a potentially sex-determining, dominant negative Hint dimerization partner whose substrate-interacting residues were specifically altered in evolution. To test the hypothesis that Gln127 of Asw is responsible for depression and/or alteration of Hint enzyme activity, a corresponding mutant was created in the chicken Hint homodimer and a novel substrate was developed that links reversal of lysine modification to aminomethylcoumarin release. Strikingly, the Hint-W123Q substitution reduced kcat/Km for AMP-lysine hydrolysis 17-fold, while it increased specificity for AMP-paranitroaniline hydrolysis by 160-fold. The resulting 2700-fold switch in enzyme specificity suggests that Gln127 could be the dominant component of Asw dominant negativity in avian feminization.




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