Freie Universität Berlin, Berlin, Germany.
Charité-Universitätsmedizin Berlin and Freie Universität Berlin, Berlin, Germany.
Arthritis Rheumatol. 2016 May;68(5):1172-82. doi: 10.1002/art.39567.
Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA-B27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x-ray crystallographic data showed that peptides can be displayed by almost identical HLA-B27 molecules in a subtype-dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self-peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B27:09 (which is not associated with AS), while B27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B27:04 and B27:06, another pair of minimally distinct HLA-B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS.
Using x-ray crystallography, we determined the structures of the pVIPR-B27:04 and pVIPR-B27:06 complexes and used isotope-edited infrared (IR) spectroscopy to probe the dynamics of these HLA-B*27 subtypes.
As opposed to B27:05 and B27:09, B27:04 (which is associated with AS) displays pVIPR conventionally and B27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA-B27 subtypes using IR spectroscopy revealed that B27:04 and B27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B27:06 and B*27:09.
Our results demonstrate that an increase in conformational flexibility characterizes the disease-associated subtypes B27:04 and B27:05.
已知抗原加工和呈递的差异有助于 HLA-B27 亚型与炎症性风湿病强直性脊柱炎 (AS) 的不同关联。支持这一观点，先前的 X 射线晶体学数据表明，肽可以通过几乎相同的 HLA-B27 分子以亚型依赖的方式显示，使细胞毒性 T 淋巴细胞能够区分这些亚型。例如，源自血管活性肠肽受体 1（pVIPR；序列 RRKWRRWHL）的人类自身肽由 B27:09（与 AS 无关）以单一构象显示，而 B27:05（与 AS 相关）以双结合模式呈现该肽。此外，这些亚型之间构象灵活性的差异可能会影响它们的稳定性或抗原呈递能力。本研究旨在研究另一对最小差异的 HLA-B27 亚型 B27:04 和 B*27:06，以评估双肽构象或结构动力学是否在 AS 的起始中起作用。
使用 X 射线晶体学确定了 pVIPR-B27:04 和 pVIPR-B27:06 复合物的结构，并使用同位素编辑红外（IR）光谱法探测这些 HLA-B*27 亚型的动力学。
与 B27:05 和 B27:09 相反，与 AS 相关的 B27:04（与 AS 相关）以常规方式显示 pVIPR，而 B27:06（与 AS 无关）以双构象呈现该肽。使用 IR 光谱法比较 4 种 HLA-B27 亚型发现，与非相关亚型 B27:06 和 B27:09 相比，B27:04 和 B*27:05 的分子动力学升高。
我们的结果表明，构象灵活性的增加是疾病相关亚型 B27:04 和 B27:05 的特征。
