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Call For Papers: Comparative Genomics

Altered specificity of Hint-W123Q supports a role for Hint inhibition by ASW in avian sex determination

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

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-para-nitroaniline 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.

AMP-lysine hydrolase; W chromosome; dominant negative; site-directed mutagenesis

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