Abstract
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs therefore requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies.
Highlights
Our human body is continually threatened by billions of potential pathogens, e.g., bacteria, viruses, fungi, and parasites
This review focuses on the structure and dynamics of antigenic peptides bound to transporter associated with antigen processing (TAP), shedding light on recent efforts to determine the structure of a bound substrate and to localize its respective binding site by biophysical and theoretical methods, such as electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), and molecular docking experiments
This study proposed that peptides bind to TAP in a β-hairpin-like conformation parallel to the membrane plane [46], which is contrary to EPR distance constraints on TAP-bound peptides [29] and docking studies [45]
Summary
Our human body is continually threatened by billions of potential pathogens, e.g., bacteria, viruses, fungi, and parasites. The non-equivalence of the two nucleotide-binding sites (NBS I and II), each coordinating an ATP molecule by both NBDs, is an intriguing feature common to many human ABC transporters including TAP (Figure 1C). Besides the well-characterized high-affinity peptide-binding site accessible in the inward-facing conformation, a second, lowaffinity binding site has been proposed based on transport studies of TAP reconstituted in proteoliposomes [41].
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