Ovalbumin(323-339) peptide binds to the major histocompatibility complex class III-Ad protein using two functionally distinct registers
Ovalbumin(323-339) peptide binds to the major histocompatibility complex class III-Ad protein using two functionally distinct registers
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DOI：
10.1021/bi991393l
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发表时间：
1999-12-14
期刊：
影响因子：
2.9
通讯作者：
Beeson, C
中科院分区：
文献类型：
--
作者：
McFarland, BJ;Sant, AJ;Beeson, C
II类主要组织相容性复合体（MHC）的蛋白质结合随后呈递给T细胞的抗原肽。先前的研究表明，鸡卵清蛋白（Ova）323-339肽与I-A（d）MHC II类蛋白结合所需的大多数残基包含在较短的325-336肽内。该观察结果与共价连接至I-A（d）的Ova肽的X射线结构（1 IAO结构）有些不一致，其中残基323和324与蛋白质形成结合相互作用。Ova（325-336）肽的第二寄存器被提出，其中残基326和327占据与1 IAO结构中的残基323和324类似的位置。发现最低限度地包含1 IAO和替代寄存器的两种Ova肽，分别为Ova（323-335）和Ova（325-336），以不同的动力学从I-A（d）解离。当MHC β链的His 81残基被天冬酰胺取代时，两种肽的解离速率都得到增强。在1 IAO结构中，β H81残基与1323的骨架羰基形成氢键。如果Ova（325-336）肽也结合在1 IAO寄存器中，则β H81侧链将没有可比较的氢键受体，这可以解释该肽对β H81置换的敏感性。在11 A 0寄存器中结合的Ova（323-335）肽不刺激由在替代寄存器中结合的Ova（325-336）刺激的T细胞杂交瘤。这些结果表明，单个肽可以在替代寄存器中结合MHC肽，产生不同的T细胞应答。
Proteins of the class II major histocompatibility complex (MHC) bind antigenic peptides that are subsequently presented to T cells. Previous studies have shown that most of the residues required for binding of the chicken ovalbumin (Ova) 323-339 peptide to the I-A(d) MHC class II protein are contained within the shorter 325-336 peptide. This observation is somewhat inconsistent with the X-ray structure of the Ova peptide covalently attached to I-A(d) (1IAO structure) in which residues 323 and 324 form binding interactions with the protein. A second register for the Ova(325-336) peptide is proposed where residues 326 and 327 occupy positions similar to residues 323 and 324 in the 1IAO structure. Two Ova peptides that minimally encompass the 1IAO and alternate registers, Ova(323-335) and Ova(325-336), respectively, were found to dissociate from I-A(d) with distinct kinetics. The dissociation rates for both peptides were enhanced when the His81 residue of the MHC beta-chain was replaced with an asparagine. In the 1IAO structure the beta H81 residue forms a hydrogen bond to the backbone carbonyl of 1323. If the Ova(325-336) peptide were also bound in the 1IAO register, there would be no comparable hydrogen-bond acceptor for the beta H81 side chain that could explain this peptide's sensitivity to the beta H81 replacement. The Ova(323-335) peptide that binds in the 1IAO register does not stimulate a T-cell hybridoma that is stimulated by Ova(325-336) bound in the alternate register. These results demonstrate that a single peptide can bind to an MHC peptide in alternate registers producing distinct T-cell responses.