NATURALLY PROCESSED PEPTIDES FROM 2 DISEASE-RESISTANCE-ASSOCIATED HLA-DR13 ALLELES SHOW RELATED SEQUENCE MOTIFS AND THE EFFECTS OF THE DIMORPHISM AT POSITION-86 OF THE HLA-DR-BETA CHAIN
NATURALLY PROCESSED PEPTIDES FROM 2 DISEASE-RESISTANCE-ASSOCIATED HLA-DR13 ALLELES SHOW RELATED SEQUENCE MOTIFS AND THE EFFECTS OF THE DIMORPHISM AT POSITION-86 OF THE HLA-DR-BETA CHAIN
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DOI：
10.1073/pnas.92.14.6567
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发表时间：
1995-07-03
影响因子：
11.1
通讯作者：
HILL, AVS
中科院分区：
文献类型：
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作者：
DAVENPORT, MP;QUINN, CL;HILL, AVS
HLA-DR 13与人类对两种主要传染病的抗性有关。为了研究两种HLA-DR 13分子的肽结合特异性以及HLA-DR β链86位的Gly/瓦尔二态性对天然肽配体的影响，从免疫亲和纯化的HLA-DRB 1 *1301和-DRB 1 *1302（仅在该位置不同的分子）中酸洗脱这些肽，通过串联MS或Edman微测序对洗脱的肽进行池测序或单个肽测序。从9种源蛋白获得23种肽的序列。每个等位基因的三个池序列和单个肽的序列用于定义每个等位基因的结合基序。结合特异性仅在主要疏水锚残基处变化，差异在于DRB 1 *1302中对芳香族氨基酸Tyr和Phe的偏好和DRB 1 *1301中对瓦尔的偏好。洗脱肽的合成类似物在它们与纯化的HLA-DR的结合中显示等位基因特异性，和Ala取代的肽用于鉴定用于结合的主要锚残基。从DRB 1：1：1302洗脱的一些肽（使用芳香族氨基酸作为初级锚的那些肽）不能结合DRB 1 *1301，这证实了由位置86处的Gly →瓦尔改变所赋予的对肽锚残基的不同偏好。这些数据表明HLA-DRB 1 *1301和DRB 1 *1302与对严重疟疾的抗性和对B型肝炎病毒感染的清除的差异关联的分子基础。
HLA-DR13 has been associated with resistance to two major infectious diseases of humans, To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position, The eluted peptides were subjected to pool sequencing or individual peptide sequencing by tandem MS or Edman microsequencing, Sequences were obtained for 23 peptides from nine source proteins, Three pool sequences for each allele and the sequences of individual peptides were used to define binding motifs for each allele, Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301, Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1:':1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly --> Val change at position 86, These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.