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The transporter associated with antigen processing (TAP) delivers peptides into the lumen of the endoplasmic reticu-lum for binding onto major histocompatibility complex class I molecules. TAP comprises two polypeptides,TAP1 andTAP2,eachwithanN-terminal transmembranedomain and a C-terminal cytosolic nucleotide binding domain (NBD). The two NBDs have distinct intrinsic nucleotide binding properties. | Eur. J. Biochem. 270 4531-4546 2003 FEBS 2003 doi 10.1046 j.1432-1033.2003.03848.x The distinct nucleotide binding states of the transporter associated with antigen processing TAP are regulated by the nonhomologous C-terminal tails of TAP1 and TAP2 Hicham Bouabe and Michael R. Knittler Institute for Genetics University of Cologne Germany The transporter associated with antigen processing TAP delivers peptides into the lumen of the endoplasmic reticulum for binding onto major histocompatibility complex class I molecules. TAP comprises two polypeptides TAPI andTAP2 each with an N-temiinal transmembratnedomain and a C-terminal cytosolic nucleotide binding domain NBD . The two NBDs have distinct intrinsic nucleotide binding properties. In the resting state of TAP the NBD1 has a much higher binding activity for ATP than the NBD2 while the binding of ADP to the two NBDs is equivalent. To attribute the different nucleotide binding behaviour of NBD1 and NBD2 to specific sequences we e nnt nued chimeric TAP1 and TAP2 polypeptides in which either the nonhomologous C-terminal tails downstream of the Walker B motif or the core NBDs which are enclosed by the conserved Walker A and B motifs were reciprocally exchanged. Our biochemical and functional studies on the different TAP chimeras show that the distinct nucleotide binding behaviour of TAP1 and TAP2 is controlled by the nonhomolo-gous C-terminal tails of the two TAP chains. In addition our data suggest that the C-terminal tail of TAP2 is required for a functional transporter by regulating ATP binding. Further experiments indicate that ATP binding to NBD2 is important because it prevents simultaneous uptake of ATP by TAP1. We propose that the C-terminal tails of TAP1 and TAP2 play a crucial regulatory role in the coordination of nucleotide binding and ATP hydrolysis by TAP. Keywords antigen presentation transporter associated with antigen processing endoplasmic reticulum peptide transport nucleotide binding domains. The .
