ABC A-Subfamily Transporters: Structure, Function and Disease ⁎ Wolfgang E
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1762 (2006) 510–524 http://www.elsevier.com/locate/bba Review ABC A-subfamily transporters: Structure, function and disease ⁎ Wolfgang E. Kaminski a, , Armin Piehler b, Jürgen J. Wenzel c a Institute for Clinical Chemistry, Faculty for Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany b Department of Clinical Chemistry, Ulleval University Hospital, 0407 Oslo, Norway c Department of Medicine II, Johannes Gutenberg-University Mainz, 55101 Mainz, Germany Received 24 October 2005; received in revised form 30 January 2006; accepted 31 January 2006 Available online 28 February 2006 Abstract ABC transporters constitute a family of evolutionarily highly conserved multispan proteins that mediate the translocation of defined substrates across membrane barriers. Evidence has accumulated during the past years to suggest that a subgroup of 12 structurally related “full-size” transporters, referred to as ABC A-subfamily transporters, mediates the transport of a variety of physiologic lipid compounds. The emerging importance of ABC A-transporters in human disease is reflected by the fact that as yet four members of this protein family (ABCA1, ABCA3, ABCR/ABCA4, ABCA12) have been causatively linked to completely unrelated groups of monogenetic disorders including familial high-density lipoprotein (HDL) deficiency, neonatal surfactant deficiency, degenerative retinopathies and congenital keratinization disorders. Although the biological function of the remaining 8 ABC A-transporters currently awaits clarification, they represent promising candidate genes for a presumably equally heterogenous group of Mendelian diseases associated with perturbed cellular lipid transport. This review summarizes our current knowledge on the role of ABC A-subfamily transporters in physiology and disease and explores clinical entities which may be potentially associated with dysfunctional members of this gene subfamily. © 2006 Elsevier B.V. All rights reserved. Keywords: ABC transporter; Lipid; Atherosclerosis; Retina; Surfactant; Ichthyosis 1. Introduction human family of ABC transporters have been identified which, based on their structural relatedness, are subdivided into 7 ATP-binding cassette (ABC) transporters constitute one of families, designated ABC A–G [1]. the largest known superfamilies of proteins [1].These Functional ABC transporters show a common global evolutionary highly conserved multispan transmembrane mole- organization. So-called full-size ABC transporters are typically cules use the energy of ATP hydrolysis to translocate a broad composed of two tandemly linked functional units [3], each spectrum of molecules across the cell membrane. Substrates that consisting of an ATP binding cassette and a transmembrane are transported by ABC molecules include lipids, peptides, domain complex. Alternatively, they can form homo- or amino acids, carbohydrates, vitamins, ions, glucuronide and heterodimers which consist of two half-size transporters that glutathione conjugates, and xenobiotics [1,2]. In eukaryotes, are encoded by distinct genes [4]. Evidence has accumulated to ABC transporters are located in the plasma membrane, in the suggest that ABC transporters exert their functions as membranes of intracellular compartments such as the Golgi, membrane associated multiunit complexes. Examples include endosome, multivesicular bodies, endoplasmic reticulum, the ABC transporter ABCC8 (SUR1) which is functionally peroxisome, and in mitochondria. To date, 48 members of the associated with the K+ channel KIR6.1 and a potassium- sensitive Ca2+-channel [5,6]. Moreover, the transporter CFTR (ABCC7) binds syntaxin 1A, a member of the syntaxin family of membrane fusion regulators [7], a sodium channel [8] and the ⁎ Corresponding author. Tel.: +49 0621 383 4012; fax: +49 0621 383 3819. endocytic adaptor complex AP-2 [9]. It is thus conceivable that E-mail address: [email protected] full-size ABC transporters, as large components of membrane (W.E. Kaminski). associated multiunit complexes, are not necessarily restricted to 0925-4439/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2006.01.011 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 511 serve one defined function but are likely involved in a spectrum cluster on chromosome 17q, it has been suggested that these of biologic activities depending on the specific assembly of the five transporters represent a separate subgroup within the A- functional complex and the biologic activities of their subfamily (“ABCA6-like transporters”) [11,12]. interaction partners. 3. ABC A-subclass transporters causing inherited diseases 2. Structural and evolutionary features of human ABC A-subclass transporters In the 1990s, considerable efforts have been made to study the role of ABC transporters in multidrug resistance in the ABCA1 and ABCA2 (formerly known as ABC1 and context of tumor cell therapy. However, the bona fide biological ABC2, respectively), the prototypic members of the ABC A- functions of most known ABC transporters remained and still subfamily, were initially co-identified by Luciani et al. [10] in remain unclear. In recent years, a series of groundbreaking the mouse. Throughout the past decade, 10 additional studies has dramatically expanded our knowledge of the role of functional genes were discovered. Based on their common ABC molecules in physiology and disease and has led to the structural features, which set them apart from other ABC systematic identification of all members of the human ABC transporters, they were categorized into a distinct subgroup— transporter gene family. the ABC A-subfamily [1]. The known 12 human ABC A- Assessment of the biological role of full-size ABC trans- transporters have been denoted ABCA1–ABCA13. The porters is a difficult task because of the complex architecture of current nomenclature is inconsistent in that since no these large molecules, their strategic position between two functional human “ABCA11” gene exists (a designation that compartments that are separated by lipid bilayers and the fact has originally been erroneously assigned to a pseudogene). that they appear to operate as part of membrane bound Structurally, all ABC A-transporters are full-size transporters multifunction complexes. Most valuable insights into their that range from 1543 to 5058 amino acids (aa) in size. A physiologic functions come from loss of function scenarios as synopsis of their biological features is shown in Table 1. With they occur in human monogenetic diseases and genetically the exception of ABCR, which is selectively expressed in the modified null mutant mice. To date, loss of function mutations retina, and ABCA13, whose expression appears to be limited in 14 ABC transporters have been causatively linked to to a small number of organs, ABC A-transporters have broad Mendelian disorders (Table 3). Interestingly, among human tissue-specificity. ABC transporters outside the A-subfamily a striking tropism Pairwise comparison of the amino acid sequences of all can be observed for diseases that manifest with defective known 12 human ABC A-subfamily members reveals exocrine/endocrine function in the liver–pancreas system. homologies ranging from 28% (ABCA8/ABCA12) to 72% These include disorders associated with dysfunctional bile (ABCA8/ABCA9) (Table 2). Phylogenetic analysis suggests secretion (progressive familial intrahepatic cholestasis types 2 that all ABC A-subclass genes have evolved from a and 3, and Dubin–Johnson syndrome caused by defective primordial ancestor gene and were subsequently dispersed ABCB4, ABCB11, and ABCC2, respectively), cystic fibrosis across the genome (Fig. 1) [1]. Of note, the transporters (CFTR/ABCC7) and familial hyperinsulinism (ABCC8) [13– ABCA5, ABCA6, ABCA8, ABCA9, and ABCA10 share 15]. Moreover, the ABC C-subfamily transporter ABCC6, strikingly high overall amino acid sequence homologies but mutations of which mainly cause a skin phenotype known as differ significantly from other ABC A-subfamily members. pseudoxanthoma elasticum, is strongly expressed in the liver Based on this and the fact that their genes form a compact and calcifications in the pancreas have also been reported [16]. Table 1 Biological features of ABC A-transporters Gene GenBank Chrom. Gene Exons Alt. spliced Cholesterol Amino Molecular accession no. localization size (kb) mRNAs responsiveness acids weight (kDa) ABCA1 NM_005502 9q31.1 147 50 nr + 2261 254 ABCA2 NM_001606 9q34.3 21 48 nr + 2436 270 ABCA3 NM_001089 16p13.3 65 33 nr ? 1704 191 ABCA4 NM_000350 1p22.1 128 50 nr − 2273 256 ABCA5 NM_018672 17q24.3 69 38 nr ? 1642 187 ABCA6 NM_080284 17q24.2–3 63 39 1 + 1617 184 ABCA7 NM_019112 19p13.3 24 46 2 + 2146 235 ABCA8 NM_007168 17q24.2 88 38 nr ? 1581 179 ABCA9 NM_080283 17q24.2 86 39 3 + 1624 184 ABCA10 NM_080282 17q24.3 97 40 4 + 1543 176 ABCA12 NM_173076 2q35 207 53 2 ? 2595 293 ABCA13 NM_152701 7p12.3 449 60 5 ? 5058 576 Accession numbers refer to the NCBI GenBank, chromsomal localizations to the UCSC Genome browser (http://genome.ucsc.edu). Gene sizes and exon numbers were determined on the basis of the respective complete cDNAs using the UCSC Genome browser (NCBI/UCSC Build 35, May 2004) and confirmed by BLAT and SIM4 alignments, respectively. Amino acid numbers and molecular weights were calculated