Powering the peptide pump: TAP crosstalk with energetic nucleotides

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2002-09, Vol.27 (9), p.454-461
• Main Authors: van Endert, Peter M, Saveanu, Loredana, Hewitt, Eric W, Lehner, Paul J
• Format: Article
• Language: English
• Subjects: ABC transporter; Adenosine Diphosphate - metabolism; Adenosine Diphosphate - physiology; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - physiology; Animals; Antigen Presentation; ATP binding cassette; ATP Binding Cassette Transporter, Subfamily B, Member 3; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - immunology; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette Transporters - physiology; Cell Membrane - immunology; Cell Membrane - metabolism; Cell Membrane - physiology; Herpes virus; HLA-B Antigens - immunology; HLA-B Antigens - metabolism; Humans; Major histocompatability class I; Major Histocompatibility Complex; Molecular Chaperones - immunology; Peptides; Protein Conformation; Transporter associated with antigen processing
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/S0968-0004(02)02090-X

ATP-binding cassette (ABC) transporters represent a large family of membrane-spanning proteins that have a shared structural organization and conserved nucleotide-binding domains (NBDs). They transport a large variety of solutes, and defects in these transporters are an important cause of human disease. TAP (ṯransporter associated with a̱ntigen p̱rocessing) is a heterodimeric ABC transporter that uses nucleotides to drive peptide transport from the cytoplasm into the endoplasmic reticulum lumen, where the peptides then bind major histocompatibility complex (MHC) class I molecules. TAP plays an essential role in the MHC class I antigen presentation pathway. Recent studies show that the two NBDs of TAP fulfil distinct functions in the catalytic cycle of this transporter. In this opinion article, a model of alternating ATP binding and hydrolysis is proposed, in which nucleotide interaction with TAP2 primarily controls substrate binding and release, whereas interaction with TAP1 controls structural rearrangements of the transmembrane pathway. Viral proteins that inhibit TAP function cause arrests at distinct points of this catalytic cycle. A model of an alternating catalytic cycle, with distinct roles of the two ATP binding cassettes, of the transporters associated with antigen processing is developed.