How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire
How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire
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DOI：
10.1073/pnas.1522069113
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
Baker, Brian M.
中科院分区：
文献类型：
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作者：
Blevins, Sydney J.;Pierce, Brian G.;Baker, Brian M.
T细胞受体（TCR）如何能够内在地偏向于MHC蛋白，同时显示出与不同配体结合所需的结构适应性，这仍然是一个有争议的难题。我们通过检查α β TCR序列和结构与MHC蛋白的物理化学相容性的证据来解决这个问题。我们发现，人类TCR富集了参与多态性的、带正电荷的“热点”区域的能力，该区域几乎是常见的人类I类MHC蛋白HLA-A*0201（HLA-A2）的α 1-螺旋所独有的。TCR结合需要热点掩埋，产生高能量的惩罚，必须通过互补的静电相互作用抵消。TCR结合环，特别是由TCR V α和V β基因编码的生殖系环中负电荷的富集提供了这种能力，并且与TCR在HLA-A2上的限制性定位相关。值得注意的是，抗体基因中不存在这种富集。这些数据表明，与HLA-A2的内置TCR相容性使受体偏向于特定的结合模式，但不强迫。我们的研究结果提供了一个指导性的例子，结构上顺从的MHC偏见可以在TCR编码。
How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining alpha beta TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the alpha 1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR V alpha and V beta genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.