CD36 Gene Structure and Regulation
The CD36 gene consists of 15 exons encompassing more than 32 kilobases on the q11.2 band of human chromosome 7 33 . Both the N- and C-terminal transmembrane and cytoplasmic domains are encoded by single exons exon III and part of exon XIV , while the extracellular domain is divided among 11 exons IV-XIV . Recently, several mRNA transcripts arising from alternative splicing of coding exons in peripheral blood monocytes have been reported 34 . The protein products of these alternate forms have...
Retinal Degeneration and ABCA4 ABCR
In addition to ABCA1, the ABCA4 ABCR gene located on chromosome 1p21 Tabs 3.1 and 3.2 is another example how several mutations in one ABC transporter gene can cause pleiotropic effects. Thus, many different clinical phenotypes, associated with various forms of eye degeneration, and the age of onset as well as disease severity are associated with distinct mutations in ABCA4 9 . As summarized in Tab. 3.2, ABCA4 has been found to be a causal gene for a series of retinal diseases. As an effort of...
The ADIFAB Assay
The ADIFAB assay makes use of a chemically modified I-FABP. A fluorescent ac-rylodan molecule, which is covalently attached to the Lys27 side-chain of rat I-FABP, is thereby employed to monitor any fluorescence-induced changes due to ligand binding. One major advantage of this procedure is that binding studies can be implemented under true equilibrium conditions. Moreover, in addition to obtaining binding constants, this method provides both kinetic and thermodynamic data such as the rate of...
Glomerular Handling of Albumin
Renal plasma flow and subsequent glomerular filtration results in the passage of water, low molecular weight solute and some macromolecules, including albumin, into the tubular fluid. The quantity of intact albumin excreted in the urine of healthy subjects is however negligible. Clearly, therefore, filtered albumin must be removed from glomerular ultrafiltrate and processed by tubular cells. It is postulated that excess albumin interacting with the proximal tubule may contribute very...
Cellular Fatty Acid Transport via FABPProtein Interactions
As noted above, in vitro studies suggested a potential for FABPs to act as targeting proteins, conveying their ligands to particular domains on organellar membranes, and or to specific protein receptors. Recently a number of protein-protein interactions involving FABPs have indeed been discovered, suggesting that fatty acids may be transported around the cell in a regulated manner. Using yeast two-hybrid assays, an interaction between A-FABP and hormonesensitive lipase HSL was discovered and...
Function of FATPs
Among the various FATP family members described to date, function in LCFA import has been demonstrated for murine isoforms mmFATPl, mmFATP2, mmFATP4, and mmFATP5 for the C. elegans ortholog ceFATPb for the M. tuberculosis ortholog mtFATP and for the S. cerevisiae ortholog fatlp 26, 28, 32 . In mammalian overexpression studies, the various FATP isoforms orthologs have been expressed in cells with low basal fatty acid import. Uptake assays have been performed by brief incubations of cells 15-60...
References
1 N. Tao, S.J. Wagner, D.M. Lublin, J. Biol. Chem. 1996, 271, 22315-22320. 2 M.A. Connelly, M. de la Llera-Moya, P. Monzo, P.G. Yancey, D. Drazul, G. Stoudt, N. Fournier, S.M. Klein, G. H. Rothblat, D. L. Williams, Biochemistry 2001, 40, 5249-5259. 3 A. Jochen, J. Hays, J. Lipid Res. 1993, 34, 1783-1792. 4 B. Podolsak, Thromb. Haemost. 1977, 37, 396-406. 5 D.E. Greenwalt, N.N. Tandon, G.A. Ja-mieson, Thromb. Haemost. 1991, 65, 1153. 6 A.S. Asch, I. Liu, F.M. Briccetti, J. W. Barnwell, F....
The ACBP Family
The ACBP is an approximately 10-kDa protein consisting of 86-92 amino acid residues depending on the species. ACBP has a highly conserved sequence and has been found in all eukaryotic species examined, ranging from yeast and plants to reptiles, birds, and mammals. Mouse and rat ACBP have 97 identity at the amino acid level, while species as diverse as humans and Saccaromyces cerevisiae exhibit 48 identity. A BLAST database search in November 2001 with the human ACBP sequence revealed 43 basal...
ABCA1 in Macrophage Lipid Transport
Several factors control the expression and activity of ABCA1. Induced cholesterol influx into macrophage cells has been shown to be a potent inducer of ABCA1 expression 40 . Since the cloning of the complete human and mouse ABCA1 genes, a number of transcriptional control elements acting via alternative promoters have been characterized 197-199 Fig. 3.6 . The ABCA1 upstream region contains a macrophage-specific promoter preceding exon 1. This sequence binds the repressors ZNF202 and USF1 2, as...
Structure of FATPs
FATP1 is a 646 amino acid protein that is expressed in cells and tissues with high-level fatty acid import for metabolism or storage 25 . Expression of FATP1 in mammalian cells increases import of radiolabeled and fluorescently labeled LCFAs and very long-chain fatty acids VLCFAs , but not medium-chain substrates. FATP1 is a member of a large family of related proteins from diverse organisms including Saccharomyces cerevisiae, Caenorhabditis elegans, Mycobacterium tuberculosis, rats, mice, and...
References Qao
1 Sellers, A.L., Katz, J, Bonorris, G, Okuyama, S. J. Lab. Clin. Med. 1966, 68, 177-185. 2 Reeve, E.B., Chen, A.Y. New York Academic Press 1970, 89-109. 3 Schneeberger, E. E., Hamelin, M. Am. J. Physiol. 1984, 247, 206-217. 4 Milici, A. J., Watrous, N. E., Stuken-brok, H., Palade, G. E. J Cell Biol 1987, 105, 2603-2612. 5 Schnitzer, J.E., Carley, W.W., Palade, G. E. Am. J. Physiol. 1988, 254, 425-437. 6 Curry, F. E. Circ. Res. 1986, 59, 367-380. 7 Michel, C.C. J. Physiol. 1988, 404, 1-29. 8...
The Calycin Superfamily
The iLBPs belong to a larger superfamily of lipid binding proteins, the so-called calycins 7 , that show a common up-and-down -barrel fold 8 . Despite amino acid sequence homologies as low as 10 , the different branches of this super-family are apparently genetically related 9 . Hence, the calycins consist of three main protein families the avidins, the lipocalins, and the iLBPs. The avidins are biotin binding proteins from oviparous vertebrates. Their structure comprises eight antiparallel...
Cystic Fibrosis ABCC7CFTR
Cystic fibrosis, caused by mutations in ABCC7 CFTR Tab. 3.2 is one of the most frequent inherited diseases in Caucasian populations with a prevalence of 1 900 to 1 2500, whereas African and Asian individuals are affected to a much lesser extent. Interestingly, a three base pair deletion AF508 accounts for 70-80 of the mutated alleles in northern European populations. The total number now comprises more than 1000 CFTR mutations The spectrum of the disease severity is dependent on the residual...
ABCG1 and Other ABCG Members in Sterol Homeostasis
Following its cloning in 1996 112 , it was four years before ABCG1 attracted great attention because of its striking similarities with ABCA1 in its expression pattern in monocytic cells. Using a differential display approach ABCG1 was identified as a target gene involved in macrophage lipid homeostasis 41 . Like ABCA1 40 , ABCG1 is upregulated during the differentiation process of monocytes into mature macrophages and is strongly induced by foam cell conversion of these macrophages under sterol...
Albumin Receptors Structure and Function 79
4.2 The Search for an Albumin Receptor 80 4.2.1 The Endothelium-Albumin Relationship Early Concepts 80 4.2.2 Identification of Receptors for Native and Modified Albumin in Endothelial Cells 81 4.3 Albumin Receptors in the Kidney 83 4.3.1 Glomerular Handling of Albumin 83 4.3.2 Binding and Uptake ofAlbumin in the Kidney Proximal Tubule 83 4.4 Megalin and Cubilin as Proximal Tubule Albumin Receptors S4 4.5 Albumin as a Signaling Molecule -Implications for Albumin Receptor Function S 4.5.1 LDLR...
The Lipidex Assay
The first binding assay for FABPs was based on the Lipidex procedure developed by Glatz and Veerkamp 142 , which uses a lipophilic Sephadex material hydroxyalkoxypropyl dextran to sequester small hydrophobic molecules from aqueous solution. This material can therefore be employed to delipidate iLBPs after protein purification, in order to subsequently study protein lipid complex formation with 14C-labeled fatty acids. The dissociation constants Kd thus obtained for various fatty acid FABP...
CD36 and Platelet Function
When vascular injury occurs, binding to the exposed collagen and fibronectin of the subendothelial matrix induces platelet activation. This is associated with platelet degranulation and the release of coagulation factors and adhesive proteins such as TSP-1, which mediate further platelet binding and aggregation. CD36 is a major glycoprotein on the surface of platelets and an adhesive receptor for both collagen and TSP-1. As a result it is likely to play a role in both platelet activation and in...
The ABCE OABP and ABCF GCN20 Subfamilies
This subfamily contains four half-size ABC transporters, which are ubiquitously expressed in human tissues and do not possess transmembrane domains. The ABCE1 gene encodes an oligoadenylate binding protein OABP , which is only found in multicellular eukaryotes and seems to participate in innate immune defense 30 . Oligoadenylates, which are produced from virus-infected cells are activators of RNaseL, which in turn degrades cellular RNAs and thereby blocks protein synthesis in infected cells....
LDLR Family as Signaling Receptors
The enigmatic effects of albumin described above could be explained by signaling through an albumin receptor. Cubilin, being an entirely extracellular protein without any transmembrane or intracellular region is unlikely to be involved in signaling. Members of the LDL-R family such as megalin are much more likely candidates. The cytoplasmic tails of the LDL-R family share homologous sequences, particularly internalization related xNPxY motifs 81 . Traditionally, members of this family have been...
ABC Transporters involved in Hepatobiliary Transport
The formation of bile is an elementary physiological function of the liver, which involves numerous transport proteins located in the basolateral sinusoidal and apical canalicular membranes of hepatocytes Fig. 3.9 . Bile, which is composed of bile salts, phospholipids, cholesterol, bilirubin and many other small molecules, is necessary for the micellar absorption of lipids from the intestine as well as for the excretion of endogenous and xenobiotic compounds 228 . The first step in...
CD36 and Malaria
The World Health Organization recognizes malaria as one of the world's primary health problems, causing more mortality than any other parasitic disease. More than 40 of the earth's population is at risk for malaria and an estimated 300500 million clinical cases each year result in 1.1 to 2.7 million deaths 88 . Almost 90 of these deaths occur in sub-Saharan Africa, and young children are the most affected. Malaria is an acute and chronic protozoan infection of the red blood cell. Of the four...