Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation

• Published in: Nature communications Vol. 13; no. 1; pp. 5470 - 13
• Main Authors: Jiang, Jiansheng, Taylor, Daniel K., Kim, Ellen J., Boyd, Lisa F., Ahmad, Javeed, Mage, Michael G., Truong, Hau V., Woodward, Claire H., Sgourakis, Nikolaos G., Cresswell, Peter, Margulies, David H., Natarajan, Kannan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 101/6; 140/131; 631/250/21; 631/45/470/1981; 631/45/611; 631/535/1266; 82/103; Antibodies; Antigen Presentation; Antigens; Crystal structure; Destabilization; Grooves; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - metabolism; HLA-B Antigens; Humanities and Social Sciences; Humans; Immunoglobulins; Immunoglobulins - metabolism; Major histocompatibility complex; multidisciplinary; Peptides; Peptides - chemistry; Protein Binding; Recognition; Science; Science (multidisciplinary); Tapasin; β2 Microglobulin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33153-8

Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin–MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the β 2 -microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and β 2 -microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange. The catalytic chaperone tapasin assists peptide loading onto MHC-I molecules for antigen presentation and immune recognition. Here, the authors present crystal structures that provide insights into the molecular mechanism of tapasin-mediated peptide exchange.