Structure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch.
Structure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch.
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DOI：
10.1073/pnas.2202209119
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发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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磷脂酶A2受体（PLA2R）是引起罕见的自身免疫性肾病膜性肾病（MN）的主要自身抗原。PLA2R自身抗体主要结合位于PLA2R的富含半胱氨酸的结构域中的28个氨基酸肽内的优势表位。我们产生了一个最小的肽结合自身抗体所需的高亲和力开发未来的治疗。我们报告了PLA2R的高分辨率结构及其结构域方向，并定义了MN中对其免疫原性至关重要的结构域表位内的关键区域。膜性肾病是一种自身免疫性肾病，由靶向肾小球足细胞上存在的抗原的自身抗体引起，引发导致肾小球损伤的级联反应。膜性肾病中最常见的循环自身抗体是针对磷脂酶A2受体（PLA2R）的，PLA2R是一种细胞表面受体。PLA2R中的优势表位位于富含半胱氨酸的结构域内，但缺乏基于高分辨率结构的定位。在这项研究中，我们定义了关键的非冗余氨基酸的PLA2R参与自身抗体结合的优势表位。我们进一步描述了用于药物发现的表位的合成肽的显性表位和间隔区要求内的两个基本区域。此外，使用冷冻电子显微镜，我们已经确定了PLA2R的高分辨率结构，分辨率为3.4 μ m，这表明在富含半胱氨酸的结构域内的优势表位和关键残基在细胞表面是可接近的。此外，PLA2R的结构不仅表明结构域的不同取向，而且还暗示PLA2R中负责诱导自身抗体形成和识别的独特免疫原性特征。
Phospholipase A2 receptor (PLA2R) is the major autoantigen responsible for causing the rare autoimmune kidney disease, membranous nephropathy (MN). PLA2R autoantibodies primarily bind to a dominant epitope located within a 28-amino acid peptide in the cysteine-rich domain of PLA2R. We generated a minimal peptide necessary for binding autoantibodies with high affinity for developing future therapies. We report the high-resolution structure of PLA2R with its domain orientation and define key regions within the domain epitope critical for its immunogenicity in MN. Membranous nephropathy is an autoimmune kidney disease caused by autoantibodies targeting antigens present on glomerular podocytes, instigating a cascade leading to glomerular injury. The most prevalent circulating autoantibodies in membranous nephropathy are against phospholipase A2 receptor (PLA2R), a cell surface receptor. The dominant epitope in PLA2R is located within the cysteine-rich domain, yet high-resolution structure-based mapping is lacking. In this study, we define the key nonredundant amino acids in the dominant epitope of PLA2R involved in autoantibody binding. We further describe two essential regions within the dominant epitope and spacer requirements for a synthetic peptide of the epitope for drug discovery. In addition, using cryo-electron microscopy, we have determined the high-resolution structure of PLA2R to 3.4 Å resolution, which shows that the dominant epitope and key residues within the cysteine-rich domain are accessible at the cell surface. In addition, the structure of PLA2R not only suggests a different orientation of domains but also implicates a unique immunogenic signature in PLA2R responsible for inducing autoantibody formation and recognition.
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DOI：
10.1074/jbc.ra120.016451
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Gully BS;Venugopal H;Fulcher AJ;Fu Z;Li J;Deuss FA;Llerena C;Heath WR;Lahoud MH;Caminschi I;Rossjohn J;Berry R
通讯作者：
Berry R
影响因子：
56.9
作者：
Beyer, Mario;Nesterov, Alexander;Breitling, Frank
通讯作者：
Breitling, Frank
影响因子：
6
作者：
Gauckler P;Shin JI;Alberici F;Audard V;Bruchfeld A;Busch M;Cheung CK;Crnogorac M;Delbarba E;Eller K;Faguer S;Galesic K;Griffin S;van den Hoogen MWF;Hrušková Z;Jeyabalan A;Karras A;King C;Kohli HS;Mayer G;Maas R;Muto M;Moiseev S;Odler B;Pepper RJ;Quintana LF;Radhakrishnan J;Ramachandran R;Salama AD;Schönermarck U;Segelmark M;Smith L;Tesař V;Wetzels J;Willcocks L;Windpessl M;Zand L;Zonozi R;Kronbichler A;RITERM study group
通讯作者：
RITERM study group
影响因子：
2.5
作者：
Basham M;Filik J;Wharmby MT;Chang PC;El Kassaby B;Gerring M;Aishima J;Levik K;Pulford BC;Sikharulidze I;Sneddon D;Webber M;Dhesi SS;Maccherozzi F;Svensson O;Brockhauser S;Náray G;Ashton AW
通讯作者：
Ashton AW
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD