A model for the nucleotide-binding domains of ABC transporters based on the large domain of aspartate aminotransferase.
ABC transporters are a large superfamily of integral membrane proteins involved inATP-dependent transport across biological membranes. Members of this superfamily play roles in a number of phenomena of biomedical interest, including cystic fibrosis (CFTR) and multidrug resistance (P-glycoprotein, MRP). Most ABC transporters are predicted to consist of four domains, two membrane-spanning domains and two cytoplasmic domains. The latter contain conserved nucleotide-binding motifs. Attempts to determine the structure of ABC transporters and of their separate domains are in progress but have not yet been successful. To aid structure determination and possibly learn more about the domain boundaries, we set out to model nucleotide-binding domains (NBDs) of ABC transporters based on a known structure. Previous attempts to predict the 3D structure of NBDs were based solely on sequence similarity with known nucleotide-binding folds. We have analyzed the sequences of a number of nucleotide-binding domains with the algorithm THREADER, developed by D.T. Jones, and a possible fold was found in the structure of aspartate aminotransferase. We present a model for the N-terminal NBD of CFTR, based on the large domain of the A chain of aspartate aminotransferase. The model is refined using multiple sequence alignment, secondary structure prediction, and 3D-1D profiles. Our model seems to be in good agreement with known properties of nucleotide-binding domains and has some appealing characteristics compared with the previous models.
Hoedemaeker
F J
FJ
Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Canada.
Davidson
A R
AR
Rose
D R
DR
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D000465:Algorithms; D000595:Amino Acid Sequence; D001219:Aspartate Aminotransferases / Q000737:chemistry*; D001665:Binding Sites / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009711:Nucleotides / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; D009711:Nucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D001219:Aspartate Aminotransferases