Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux |
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Authors: | See Raymond H Caday-Malcolm Rosalinda A Singaraja Roshni R Zhou Steven Silverston Anthony Huber Mary T Moran Josh James Erick R Janoo Rozmin Savill Jane M Rigot Veronique Zhang Lin-Hua Wang Minghan Chimini Giovanna Wellington Cheryl L Tafuri Sherrie R Hayden Michael R |
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Affiliation: | Center for Molecular Medicine and Therapeutics, Department of Medical Genetics and Children's and Women's Hospital, University of British Columbia, Vancouver, Canada. |
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Abstract: | ATP-binding cassette A1 (ABCA1) is a key mediator of cholesterol and phospholipid efflux to apolipoprotein particles. We show that ABCA1 is a constitutively phosphorylated protein in both RAW macrophages and in a human embryonic kidney cell line expressing ABCA1. Furthermore, we demonstrate that phosphorylation of ABCA1 is mediated by protein kinase A (PKA) or a PKA-like kinase in vivo. Through site-directed mutagenesis studies of consensus PKA phosphorylation sites and in vitro PKA kinase assays, we show that Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ApoA-I-dependent phospholipid efflux was decreased significantly by mutation of Ser-2054 alone and Ser-1042/Ser-2054 but was not significantly impaired with Ser-1042 alone. The mechanism by which ABCA1 phosphorylation affected ApoA-I-dependent phospholipid efflux did not involve either alterations in ApoA-I binding or changes in ABCA1 protein stability. These studies demonstrate a novel serine (Ser-2054) on the ABCA1 protein crucial for PKA phosphorylation and for regulation of ABCA1 transporter activity. |
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