Characterizing the N-terminal processing motif of MHC class I ligands.
Most peptide ligands presented by MHC class I molecules are the product of an intracellular pathway comprising protein breakdown in the cytosol, transport into the endoplasmic reticulum, and successive N-terminal trimming events. The efficiency of each of these processes depends on the amino acid sequence of the presented ligand and its precursors. Thus, relating the amino acid composition N-terminal of presented ligands to the sequence specificity of processes in the pathway gives insight into the usage of ligand precursors in vivo. Examining the amino acid composition upstream the true N terminus of MHC class I ligands, we demonstrate the existence of a distinct N-terminal processing motif comprising approximately seven residues and matching the known preferences of proteasome and TAP, two key players in ligand processing. Furthermore, we find that some residues, which are preferred by both TAP and the proteasome, are underrepresented at positions immediately preceding the N terminus of MHC class I ligands. Based on experimentally determined aminopeptidase activities, this pattern suggests trimming next to the final N terminus to take place predominantly in the endoplasmic reticulum.
Schatz
Mark M
MM
Institut für Immunologie, Johannes-Gutenberg-Universität Mainz, Mainz, Germany.
Peters
Björn
B
Akkad
Nadja
N
Ullrich
Nina
N
Martinez
Alejandra Nacarino
AN
Carroll
Oliver
O
Bulik
Sascha
S
Rammensee
Hans-Georg
HG
van Endert
Peter
P
Holzhütter
Hermann-Georg
HG
Tenzer
Stefan
S
Schild
Hansjörg
H
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003600:Cytosol / Q000201:enzymology / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000276:immunology; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; C073119:TAP1 protein, human; D000626:Aminopeptidases; D046988:Proteasome Endopeptidase Complex