期刊
MOLECULAR REPRODUCTION AND DEVELOPMENT
卷 73, 期 3, 页码 361-368出版社
WILEY
DOI: 10.1002/mrd.20409
关键词
cAMP; bicarbonate; sperm; alternative splicing; capacitation; fertility
资金
- NCI NIH HHS [5T32 CA062948, T32 CA062948] Funding Source: Medline
- NICHD NIH HHS [HD42060, HD38722, R01 HD038722] Funding Source: Medline
- NIGMS NIH HHS [R01 GM062328, GM62328] Funding Source: Medline
Soluble adenylyl cyclase is an evolutionarily conserved bicarbonate sensor that plays a crucial role in cAMP dependent processes that occur during mammalian fertilization. sAC protein is expressed at the highest levels in male germ cells, and is found to occur as one of two known isoforms: a truncated protein (sAC(t)) that consists almost exclusively of the two conserved catalytic domains (C1 and C2), and a full-length form (sAC(fl)) that contains an additional noncatalytic C-terminal region. Several studies suggested sAC(t) was more active than sAC(fl). We now demonstrate that the specific activity of sAC(t) is at least 10-fold higher than the specific activity of sAC(fl). Using deletion analysis and a novel genetic screen to identify activating mutations, we uncovered an autoinhibitory region just C-terminal to the C2 domain. Kinetic analysis of purified recombinant sAC revealed this autoinhibitory domain functions to lower the enzyme's V-max without altering its affinity for substrate or regulation by any of the known modulators of sAC activity. Our results identify an additional regulatory mechanism specific to the sAC(fl) isoform.
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