Comparative structural analysis of HLA-A2 antigens distinguishable by cytotoxic T lymphocytes: variants M7 and DR1.
Comparative structural analysis of HLA-A2 antigens distinguishable by cytotoxic T lymphocytes: variants M7 and DR1.
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可通过细胞毒性 T 淋巴细胞区分的 HLA-A2 抗原的比较结构分析：变体 M7 和 DR1。
DOI：
10.1021/bi00267a042
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发表时间：
1982
期刊：
影响因子：
2.9
通讯作者：
Strominger,JL
中科院分区：
文献类型：
--
作者：
Krangel,MS;Taketani,S;Biddison,WE;Strong,DM;Strominger,JL
Michael S. Krangel、* Shigeru Taketani、William E. Biddison、Douglas M. Strong 和 Jack L. Strominger 摘要：比较一级结构分析已开始阐明主要组织相容性复合物的 I 类抗原的多态残基和片段，其中至少有一些可能有助于免疫识别事件中重要的决定因素。已经描述了 HLA-A2 结构变体，其在血清学上与其他 HLA-A2 抗原无法区分，但既不能被 HLA-A2 特异性同种免疫细胞识别，也不能被 HLA-A2 限制性病毒免疫细胞毒性 T 淋巴细胞识别。本研究利用双标记胰蛋白酶肽比较并结合常规分析和微序列分析来研究两种此类变体 M7 和 DR1 的结构。我们发现这些变体彼此相同，但与主要的 HLA-A2 重链种类的不同之处在于残基 43 处的谷氨酰胺替换为精氨酸、跨越残基 147-157 的胰蛋白酶肽中的未识别替换以及糖基化方面尚未明确的改变。来自这些和其他变体的结构信息应该有助于精确定义分子上功能上重要的决定因素。由主要组织相容性复合体 (MHC) 1 编码的 I 类分子是存在于所有有核细胞上的高度多态性细胞表面抗原 (Klein, 1979)。这些分子携带对同种异体细胞毒性T淋巴细胞(CTL)对靶细胞的免疫识别很重要的外来决定因子，以及对自我限制性CTL对靶细胞的免疫识别很重要的自决定因子。后者已被证明可用于响应病毒感染细胞、化学修饰细胞和微小组织相容性抗原差异的 CTL（Dickmeiss 等，1977；Goulmy 等，1977；McMichael 等，1977；Biddison 等，1980a；Shearer & Schmitt-Verhulst，1977；Zinkernagel & Doherty， 1979）。人类 I 类抗原（HLA-A、-B 和 -C）由多态性、MHC 编码的 44 000 道尔顿重链组成，该重链被发现与不变的、非 MHC 编码的 12000 道尔顿轻链/32-微球蛋白 (02m) 非共价关联（Ploegh 等人，1981）。重链是一种跨膜糖蛋白，由大的氨基末端胞外部分、嵌入脂质双层中的一小段疏水氨基酸和小的胞内羧基末端亲水区域组成。一级结构分析表明，重链的胞外部分可以被组织成三个不同的折叠结构域(a1、a2和a3)，每个折叠结构域大约有90个氨基酸。两个氨基末端结构域a1和a2是多态性的，并且在这些结构域内可以定义或多或少的离散序列变异片段。第三个胞外结构域 a3 相对非多态性； a3 和 02m 均与免疫球蛋白恒定区结构域显示出高水平的序列同源性。据推测，重要的识别决定簇将映射到氨基末端结构域的多态性片段。然而，由于即使是两种高度交叉反应的组织相容性抗原 HLA-A2 和 HLA-A28 也存在至少 10 个氨基酸取代的差异（Lopez de Castro 等人，1982），有关此类结论的结论来自哈佛大学生物化学和分子生物学系，哈佛大学，剑桥，马萨诸塞州 02138（MSK、ST 和 JLS）、国家神经和交流研究所神经免疫学分部疾病和中风，美国国立卫生研究院，贝塞斯达，马里兰州 20205 (WEB)，以及……
Michael S. Krangel,* Shigeru Taketani, William E. Biddison, Douglas M. Strong, and Jack L. Strominger abstract: Comparative primary structural analyses have begun to elucidatepolymorphic residues and segments of the class I antigens of the major histocompatibility complex, at least some of which presumably contribute to determinants important in immune recognition events. HLA-A2 structural variants have been described which are serologically indistinguishable from other HLA-A2 antigens, yet which can be recognized neither by HLA-A2 specific alloimmune nor by HLA-A2 restricted, virus immune cytotoxic T lymphocytes. This study utilizes double-label tryptic peptide comparisons in combination with both conventional and microsequence analyses to investigate the structure of two such variants, M7 and DR1. Wefind that these variants are identical with each other and differ from the predominant HLA-A2 heavy chain species by a glutamine to arginine substitution at residue 43, by an unidentified substitution in the tryptic peptide spanning residues 147-157, and by an as yet poorly defined alteration in glycosylation. Structural information from these andother variants should be useful in precisely defining functionally important determinants on the molecule. e class I molecules encoded by the major histocompatibility complex (MHC) 1 are highly polymorphic cellsurface antigens present on all nucleatedcells (Klein, 1979). These molecules carry the foreign determinants important in immune recog-nition of target cells by alloreactivecytotoxic T lymphocytes (CTLs), as well as the self-determinants important in immune recognition of target cells by self-restricted CTLs. The latter has been demonstrated for CTLs responding to virally infected cells, chemically modified cells, and minor histocompatibility antigen differences (Dickmeiss et al., 1977; Goulmy et al., 1977; McMichael et al., 1977; Biddison et al., 1980a; Shearer & Schmitt-Verhulst, 1977; Zinkernagel & Doherty, 1979). The human class I antigens (HLA-A,-B, and-C) are composed of a polymorphic, MHC-encoded heavy chain of 44 000 daltonswhich is found noncovalently associated with an invariant, non-MHC-encoded light chain of 12000 daltons,/32-microglobulin (02m)(Ploegh et al., 1981). The heavy chain is a transmembrane glycoprotein consisting of a large amino-terminal extracellular portion, a short stretch of hydrophobic amino acids which are embedded in the lipid bilayer, and a small intracellular, carboxy-terminal hydrophilic region. Primary structural analysis suggests that the extracellular portion of the heavychain may be organized into three distinct folding domains (al, a2, and a3) of approximately 90 amino acids each. The two amino-terminal domains, al and a2, are polymorphic, and within these domains more or less discrete segments of sequence variation may be defined. The third of the extracellular domains, a3, is relatively nonpolymorphic; both a3 and 02m displayhigh levels of sequence homology with immunoglobulin constant region domains. It is presumed that important recognition determinants will map to polymorphic segments of the amino-terminal domains. However, since even two highly cross-reactive histocompatibility antigens, HLA-A2 and-A28, differ by at least ten amino acid substitutions (Lopez de Castro et al., 1982), conclusions concerning such deter-tFrom the Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, Massachusetts02138 (MSK, ST, and JLS), the Neuroimmunology Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20205 (WEB), and the …