The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1
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University of Cincinnati / OhioLINK
2010
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12825755982021-08-03T06:14:20Z The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 Smith, Loren E. Molecular Biology apolipoprotein ATP-binding cassette transporter A1 ABCA1 HDL high density lipoprotein protein <p>High density lipoprotein (HDL) plasma levels are inversely correlated with the risk of developing cardiovascular disease. HDL is formed when lipid-free apolipoproteins in the plasma accept excess phospholipids and cholesterol from cells such as hepatocytes, enterocytes, and macrophages. This process is mediated by a cell membrane protein known as ATP-binding cassette transporter A1 (ABCA1). It is unknown what structural elements in apolipoproteins allow them to participate in ABCA1-mediated cholesterol efflux. The hypothesis tested in this work is that amphipathic and charged helical structural elements of exchangeable apolipoproteins allow these proteins to facilitate ABCA1-mediated cholesterol efflux at the cell surface. Recently, it was proposed that a negatively charged and a hydrophobic surface patch on apolipoprotein (apo) A-I were important in this process (1). Our data shows that neither of these surface patches plays an important functional role in apoA-I promoted cholesterol efflux via ABCA1. It has also been proposed that a linear array of acidic amino acids aligned along the junction of the hydrophobic and hydrophilic faces of two amphipathic α-helices is the critical element for this process (2). However, studies using apoC-I point mutants demonstrated that this element was also functionally unnecessary. Instead, our studies with peptides modeling the amphipathic α-helices of apoA-II and apoC-I have shown that the minimal structural unit in apolipoproteins which allows them to serve as cholesterol acceptors in ABCA1-medated efflux is a bihelical peptide composed of an amphipathic non-lipid binding helix joined to an amphipathic fast lipid binding helix. In apoA-I, apoA-II, apoC-I, and likely apoE this structural element is found at the extreme C-terminus of the protein with the fast lipid binding helix being closest to the C-terminus. It was found that the non-lipid binding helix altered the phospholipid binding preference of the fast lipid binding helix, perhaps directing the fast lipid binding helix towards areas of the cell membrane with more tightly-packed phospholipids.</p><p>Having identified the minimal apolipoprotein structure necessary for ABCA1-mediated cholesterol efflux, it was important to next identify the location of the lipid transfer to apolipoproteins. Recently it was proposed that this lipidation process occurs through a retroendocytosis pathway (3). In this pathway apolipoproteins are endocytosed into the cell with ABCA1, lipidated intracellularly, and exocytosed as nascent HDL. Using fluorescently-labeled and radiolabeled apoA-I, we found that in non-lipid loaded cells, a majority of the endocytosed apoA-I is resecreted into the media in a degraded form. Indeed, only 11% of the HDL produced in a three hour period could be accounted for by ABCA1-mediated retroendocytosis of apoA-I. This data clearly demonstrates that, at least in non-lipid loaded cells, retroendocytosis of apoA-I is not the main pathway of HDL biogenesis.</p><p>These studies further our understanding of the mechanism of ABCA1-mediated cholesterol efflux by demonstrating that apolipoproteins utilize a bihelical non-lipid binding/fast lipid binding motif to serve as cholesterol acceptors, and that this lipidation process occurs at the cell surface.</p> 2010-12-06 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575598 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575598 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Molecular Biology apolipoprotein ATP-binding cassette transporter A1 ABCA1 HDL high density lipoprotein protein |
| spellingShingle |
Molecular Biology apolipoprotein ATP-binding cassette transporter A1 ABCA1 HDL high density lipoprotein protein Smith, Loren E. The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| author |
Smith, Loren E. |
| author_facet |
Smith, Loren E. |
| author_sort |
Smith, Loren E. |
| title |
The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| title_short |
The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| title_full |
The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| title_fullStr |
The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| title_full_unstemmed |
The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1 |
| title_sort |
interplay between apolipoproteins and atp-binding cassette transporter a1 |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575598 |
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AT smithlorene theinterplaybetweenapolipoproteinsandatpbindingcassettetransportera1 AT smithlorene interplaybetweenapolipoproteinsandatpbindingcassettetransportera1 |
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