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

Kristen P Parks; Heather Seidle; Nathan Wright; Jeffrey B Sperry; Pawel Bieganowski; Konrad Howitz; Dennis L Wright; Charles Brenner

doi:10.1152/physiolgenomics.00204.2004

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

Journal article

Open access

Peer reviewed

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

Kristen P Parks, Heather Seidle, Nathan Wright, Jeffrey B Sperry, Pawel Bieganowski, Konrad Howitz, Dennis L Wright and Charles Brenner

Physiological genomics, Vol.20(1), pp.12-14

12/15/2004

DOI: 10.1152/physiolgenomics.00204.2004

PMCID: PMC2556054

PMID: 15507519

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Abstract

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.

Hydrolases - genetics

Models, Chemical

Adenosine Monophosphate - chemistry

Substrate Specificity

Male

Dose-Response Relationship, Drug

Sex Determination Processes

Genes, Dominant

Karyotyping

Female

Glutamine - chemistry

Dimerization

Expressed Sequence Tags

Carrier Proteins - physiology

Protein Structure, Tertiary

Birds

Sex Chromosomes - ultrastructure

Hydrolysis

Animals

Chickens

Avian Proteins

Hydrolases - chemistry

Aniline Compounds - chemistry

Kinetics

Mutation

Lysine - chemistry

Evolution, Molecular

Details

Title: Subtitle: Altered specificity of Hint-W123Q supports a role for Hint inhibition by ASW in avian sex determination
Creators: Kristen P Parks - Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
Heather Seidle
Nathan Wright
Jeffrey B Sperry
Pawel Bieganowski
Konrad Howitz
Dennis L Wright
Charles Brenner
Resource Type: Journal article
Publication Details: Physiological genomics, Vol.20(1), pp.12-14
DOI: 10.1152/physiolgenomics.00204.2004
PMID: 15507519
PMCID: PMC2556054
NLM abbreviation: Physiol Genomics
ISSN: 1531-2267
eISSN: 1531-2267
Publisher: United States
Grant note: R01 CA075954 / NCI NIH HHS R01 CA075954-07 / NCI NIH HHS CA-75954 / NCI NIH HHS
Language: English
Date published: 12/15/2004
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788596102771

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