title: A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments.
abstract: The ATP binding cassette, class A (ABCA) proteins are homologous polytopic transmembrane transporters that function as lipid pumps at distinct subcellular sites in a variety of cells. Located within the N terminus of these transporters, there exists a highly conserved xLxxKN motif of unknown function. To define its role, human ABCA3 was employed as a primary model representing ABCA transporters, while mouse ABCA1 was utilized to support major findings. Transfection studies showed colocalization of both transporters with surfactant protein C (SP-C), a marker peptide for successful protein targeting to lysosomal-like organelles. In contrast, alanine mutation of xLxxKN resulted in endoplasmic reticulum retention. As proof of principle, swapping xLxxKN for the known lysosomal targeting motif of SP-C resulted in post-Golgi targeting of the SP-C chimera. However, these products failed to reach their terminal processing compartments, suggesting that the xLxxKN motif only serves as a Golgi exit signal. We propose a model whereby an N-terminal signal sequence, xLxxKN, directs ABCA transporters to a post-Golgi vesicular sorting station where additional signals may be required for selective delivery of individual transporters to final subcellular destinations.
authors.affiliation: Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.forename: Arie
authors.initials: A
authors.lastname: Hawkins
authors.forename: Henry
authors.initials: H
authors.lastname: Shuman
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Newitt
authors.forename: Jean Ann
authors.initials: JA
authors.lastname: Maguire
authors.forename: Wenge
authors.initials: W
authors.lastname: Ding
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids; D021382:Protein Sorting Signals / Q000502:physiology*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D037721:Pulmonary Surfactant-Associated Protein C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; C441524:ABCA3 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D021382:Protein Sorting Signals; D037721:Pulmonary Surfactant-Associated Protein C; D011993:Recombinant Fusion Proteins