Journal
PHYSIOLOGICAL GENOMICS
Volume 20, Issue 1, Pages 12-14Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00204.2004
Keywords
AMP-lysine hydrolase; W chromosome; dominant negative; site-directed mutagenesis
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Funding
- NCI NIH HHS [R01 CA075954-07, CA-75954, R01 CA075954] Funding Source: Medline
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Hint is a universally conserved, dimeric AMP-lysine hydrolase encoded on the avian Z chromosome. Tandemly repeated on the female-specific W chromosome, Asw encodes 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 AMP-lysine modification to aminomethylcoumarin release. Strikingly, the Hint-W123Q substitution reduced k(cat)/K-m for AMP-lysine hydrolysis 17-fold, while it increased specificity for AMP-paranitroaniline hydrolysis by 160-fold. The resulting 2,700-fold switch in enzyme specificity suggests that Gln127 could be the dominant component of Asw dominant negativity in avian feminization.
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