Document Detail


Phosphorylation of a pest sequence in ABCA1 promotes calpain degradation and is reversed by ApoA-I.
MedLine Citation:
PMID:  12869555     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
ATP-binding cassette transporter A1 (ABCA1), the defective molecule in Tangier disease, mediates the apoAI-dependent efflux of excess cholesterol from cells. We recently showed that ABCA1 proteolysis by calpain was dependent on a PEST sequence in the cytoplasmic region of ABCA1 and was reversed by apoA-I interaction with ABCA1. We show here that phosphorylation of ABCA1 in HEK293 cells was reduced by 63 +/- 2.4% after removal of the PEST sequence (ABCA1delPEST) or by incubation of cells with apoAI (58 +/- 3.3%). By contrast, ABCA1delPEST showed no further decrease of phosphorylation upon apoAI treatment. To assess the hypothesis that PEST sequence phosphorylation could regulate ABCA1 calpain proteolysis, we mutagenized S/T residues in the PEST sequence and identified Thr-1286 and Thr-1305 as constitutively phosphorylated residues. The ABCA1-T1286A/T1305A mutant was not degraded by calpain and was not further stabilized upon apoA-I treatment. The T1286A/T1305A mutant showed a 3.1-fold increase in cell surface expression and a 2.3-fold increase of apoAI-mediated cholesterol efflux compared with wild type ABCA1. In conclusion, we propose a mechanism of regulation of ABCA1 cell surface expression and function in which the interaction with apoA-I results in dephosphorylation of the ABCA1 PEST sequence and thereby inhibits calpain degradation leading to an increase of ABCA1 cell surface expression.
Authors:
Laurent O Martinez; Birgit Agerholm-Larsen; Nan Wang; Wengen Chen; Alan R Tall
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-07-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-22     Completed Date:  2003-11-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  37368-74     Citation Subset:  IM    
Affiliation:
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA. Lm2068@columbia.edu
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / chemistry*,  metabolism
Amino Acid Sequence
Apolipoprotein A-I / pharmacology*
Calpain / metabolism*
Casein Kinase II
Cyclic AMP-Dependent Protein Kinases / physiology
Humans
Molecular Sequence Data
Phosphorylation
Protein-Serine-Threonine Kinases / physiology
Grant Support
ID/Acronym/Agency:
HL22682/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Apolipoprotein A-I; EC 2.7.11.1/Casein Kinase II; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.4.22.-/Calpain

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