Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes.
Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes.
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DOI：
10.1016/j.celrep.2022.110959
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发表时间：
2022-06-14
期刊：
影响因子：
8.8
通讯作者：
Gillespie, Geraldine M.
中科院分区：
文献类型：
--
作者：
Walters, Lucy C.;Rozbesky, Daniel;Harlos, Karl;Quastel, Max;Sun, Hong;Springer, Sebastian;Rambo, Robert P.;Mohammed, Fiyaz;Yvonne Jones, E.;McMichael, Andrew J.;Gillespie, Geraldine M.
MHC- e通过向NKG2A:CD94受体展示MHC Ia类信号肽（VL9）来调节NK细胞。MHC-E还可以向CD8+ T细胞上的T细胞受体（tcr）呈递序列多样、低亲和力的病原体衍生肽。为了了解这些亲和性差异，我们比较了人MHC-E (HLA-E)-VL9与病原体来源的肽结构。小角度x射线散射（SAXS）测量溶液中的生物物理参数，允许与晶体结构进行比较。对于HLA-E-VL9， SAXS与晶体参数之间存在一致性。相比之下，hla - e结合的病原体衍生肽产生更大的SAXS尺寸，只有在提供过量肽时才会降低到其晶体尺寸。进一步的晶体学分析表明，MHC-E独有的三个氨基酸不仅使VL9靠近α2螺旋，而且通过重新配置关键的tcr相互作用α2区域，允许非VL9肽结合。因此，非VL9结合肽引入了另一种肽结合基序和表面识别景观，为VL9和非VL9- hla - e免疫区分提供了可能的基础。基于溶液的x射线散射分析显示，HLA-E结合的VL9在溶液中形成紧密折叠的形式，与病原体衍生的表位结合的HLA-E在溶液中形成异质集成。破坏的E囊占用是HLA-E结合的病原体衍生肽的特征。HLA-E α2重构为非VL9肽形成了一个共享的免疫景观。x射线结构分析显示，涉及E口袋和α2螺旋残基的中断肽相互作用在这些hla -E-肽复合物中是共享的，形成了与最佳结合的HLA-E-VL9不同的抗原识别表面。
MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination. Solution-based X-ray scattering analysis of HLA-E-bound VL9 reveals compact folded forms HLA-E bound to pathogen-derived epitopes form heterogeneous ensembles in solution Disrupted E pocket occupancy characterizes HLA-E-bound pathogen-derived peptides An HLA-E α2 reconfiguration forms a shared immune landscape for non-VL9 peptides Using small-angle X-ray scattering, Walters et al. report that HLA-E in complex with pathogen-derived peptides form heterogeneous protein ensembles in-solution. X-ray structural analysis reveals that disrupted peptide interactions involving the E pocket plus α2 helical residue are shared among these HLA-E-peptides complexes, creating antigen-recognition surfaces that diverge from optimally bound HLA-E-VL9.
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DOI：
10.1126/science.aac9475
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hansen SG;Wu HL;Burwitz BJ;Hughes CM;Hammond KB;Ventura AB;Reed JS;Gilbride RM;Ainslie E;Morrow DW;Ford JC;Selseth AN;Pathak R;Malouli D;Legasse AW;Axthelm MK;Nelson JA;Gillespie GM;Walters LC;Brackenridge S;Sharpe HR;López CA;Früh K;Korber BT;McMichael AJ;Gnanakaran S;Sacha JB;Picker LJ
通讯作者：
Picker LJ
DOI：
10.1084/jem.187.5.813
发表时间：
1998-03-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Borrego F;Ulbrecht M;Weiss EH;Coligan JE;Brooks AG
通讯作者：
Brooks AG
DOI：
10.1073/pnas.0802736105
发表时间：
2008-05-06
影响因子：
11.1
作者：
Kaiser, Brett K.;Pizarro, Juan Carlos;Strong, Roland K.
通讯作者：
Strong, Roland K.
影响因子：
4.8
作者：
Hawse, William F.;Gloor, Brian E.;Baker, Brian M.
通讯作者：
Baker, Brian M.
影响因子：
6.1
作者：
Kozin, MB;Svergun, DI
通讯作者：
Svergun, DI