Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules.
Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules.
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DOI：
10.1093/pnasnexus/pgac124
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Lizee, Gregory
中科院分区：
文献类型：
--
作者：
Jackson, Kyle R.;Antunes, Dinler A.;Talukder, Amjad H.;Maleki, Ariana R.;Amagai, Kano;Salmon, Avery;Katailiha, Arjun S.;Chiu, Yulun;Fasoulis, Romanos;Rigo, Mauricio Menegatti;Abella, Jayvee R.;Melendez, Brenda D.;Li, Fenge;Sun, Yimo;Sonnemann, Heather M.;Belousov, Vladislav;Frenkel, Felix;Justesen, Sune;Makaju, Aman;Liu, Yang;Horn, David;Lopez-Ferrer, Daniel;Huhmer, Andreas F.;Hwu, Patrick;Roszik, Jason;Hawke, David;Kavraki, Lydia E.;Lizee, Gregory
关键词：
人白细胞抗原I类（HLA-I）分子在细胞表面结合并呈递肽，以促进诱导适当的CD8+ T细胞介导的对病原体和自身来源蛋白的免疫反应。hla - 1肽结合间隙在B和F口袋中包含优势锚位点，分别主要与肽位置2和c端的氨基酸相互作用。非口袋肽- HLA相互作用也有助于肽结合和稳定性，但这些次级相互作用被认为是个体HLA同种异体或特定肽抗原所特有的。在这里，我们发现位于肽结合间隙顶部附近的两个带正电的残基促进了与所提肽第4位带负电的残基的相互作用，这种相互作用在大多数hla - 1同种异型中发生的频率较高。这些相互作用的丧失被证明会损害hla - 1 /肽结合和复合物的稳定性，正如体外和硅实验所证明的那样。此外，这些精氨酸-65 （R65）和/或赖氨酸-66 （K66）残基在HLA-A*02:01和A*24:02中的突变显著降低了hla - 1细胞表面的表达，同时也使所呈现的肽库的多样性减少了多达5倍。R65突变的影响表明，非口袋HLA-I/肽相互作用可以构成锚定基序，对HLA-I介导的抗原递呈产生意想不到的广泛影响。这些发现为肽抗原结合提供了基本的见解，可以广泛地为病毒疫苗开发和癌症免疫治疗的表位发现提供信息。
Human leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate CD8+ T cell-mediated immune responses to pathogen- and self-derived proteins. The HLA-I peptide-binding cleft contains dominant anchor sites in the B and F pockets that interact primarily with amino acids at peptide position 2 and the C-terminus, respectively. Nonpocket peptide–HLA interactions also contribute to peptide binding and stability, but these secondary interactions are thought to be unique to individual HLA allotypes or to specific peptide antigens. Here, we show that two positively charged residues located near the top of peptide-binding cleft facilitate interactions with negatively charged residues at position 4 of presented peptides, which occur at elevated frequencies across most HLA-I allotypes. Loss of these interactions was shown to impair HLA-I/peptide binding and complex stability, as demonstrated by both in vitro and in silico experiments. Furthermore, mutation of these Arginine-65 (R65) and/or Lysine-66 (K66) residues in HLA-A*02:01 and A*24:02 significantly reduced HLA-I cell surface expression while also reducing the diversity of the presented peptide repertoire by up to 5-fold. The impact of the R65 mutation demonstrates that nonpocket HLA-I/peptide interactions can constitute anchor motifs that exert an unexpectedly broad influence on HLA-I-mediated antigen presentation. These findings provide fundamental insights into peptide antigen binding that could broadly inform epitope discovery in the context of viral vaccine development and cancer immunotherapy.
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影响因子：
5.5
作者：
Bhati AP;Wan S;Hu Y;Sherborne B;Coveney PV
通讯作者：
Coveney PV
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
DOI：
10.1007/978-1-4939-7000-1_26
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Burley SK;Berman HM;Kleywegt GJ;Markley JL;Nakamura H;Velankar S
通讯作者：
Velankar S
影响因子：
15.3
作者：
Baker, BM;Turner, RV;Biddison, WE
通讯作者：
Biddison, WE
影响因子：
5.5
作者：
Fytili, P.;Dalekos, G. N.;Wedemeyer, H.
通讯作者：
Wedemeyer, H.