Institute of Biochemistry, Center for Membrane Proteomics, and Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt/Main, Germany.
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9135-40. doi: 10.1073/pnas.1001308107. Epub 2010 May 3.
The recognition of virus infected or malignantly transformed cells by cytotoxic T lymphocytes critically depends on the transporter associated with antigen processing (TAP), which delivers proteasomal degradation products into the endoplasmic reticulum lumen for subsequent loading of major histocompatibility complex class I molecules. Here we have identified a single cysteinyl residue in the TAP complex that modulates peptide binding and translocation, thereby restricting the epitope repertoire. Cysteine 213 in human TAP2 was found to be part of a newly uncovered substrate-binding site crucial for peptide recognition. This residue contacts the peptide in the binding pocket in an orientated manner. The translocation complex can be reversibly inactivated by thiol modification of this cysteinyl residue. As part of an unexpected mechanism, this residue is crucial in complementing the binding pocket for a given subset of epitopes as well as in maintaining a substrate-receptive conformation of the translocation complex.
细胞毒性 T 淋巴细胞识别病毒感染或恶性转化细胞，关键依赖于抗原加工相关转运体（TAP），该转运体将蛋白酶体降解产物输送到内质网腔中，以便随后装载主要组织相容性复合体 I 类分子。在此，我们鉴定出 TAP 复合物中的一个半胱氨酸残基可调节肽结合和转运，从而限制了表位谱。发现人 TAP2 中的半胱氨酸 213 是新发现的底物结合位点的一部分，对肽识别至关重要。该残基以定向方式与结合口袋中的肽相互作用。该转运复合物可通过该半胱氨酸残基的巯基修饰而可逆失活。作为一种意想不到的机制的一部分，该残基在补充给定表位亚群的结合口袋以及维持转运复合物的底物接受构象方面至关重要。
