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鉴定在粘蛋白样膜蛋白 HEG1 中被单克隆抗体 SKM9-2 识别的间皮瘤特异性唾液酸化表位。

Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1.

机构信息

Kanagawa Cancer Center Research Institute, Yokohama, Japan.

Glycoscience & Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.

出版信息

Sci Rep. 2018 Sep 24;8(1):14251. doi: 10.1038/s41598-018-32534-8.

DOI:10.1038/s41598-018-32534-8
PMID:30250045
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6155162/
Abstract

The anti-mesothelioma mAb SKM9-2 recognizes the sialylated protein HEG homolog 1 (HEG1). HEG1 is a 400 kDa mucin-like membrane protein found on mesothelioma. SKM9-2 can detect mesothelioma more specifically and sensitively than other antibodies against current mesothelioma markers; therefore, SKM9-2 would be likely useful for the precise detection and diagnosis of malignant mesothelioma. In the present study, we investigated the epitope of SKM9-2. We analyzed the binding of SKM9-2 to truncated HEG1 and candidate epitope-fused glycosylphosphatidylinositol-anchor proteins. The epitope of SKM9-2 was identified as an O-glycosylated region, 893-SKSPSLVSLPT-903, in HEG1. An alanine scanning assay of the epitope showed that SKM9-2 bound to a simple epitope in HEG1, and the SKxPSxVS sequence within the epitope was essential for SKM9-2 recognition. Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser and Ser. Neuraminidase treatment analysis also confirmed that the epitope in mesothelioma cells contained a similar glycan modification. The specific detection of mesothelioma with SKM9-2 can thus be performed by the recognition of sialylated glycan modification in the specific region of HEG1.

摘要

抗间皮瘤单克隆抗体 SKM9-2 识别唾液酸化蛋白 HEG 同源物 1 (HEG1)。HEG1 是一种 400kDa 的粘蛋白样膜蛋白，存在于间皮瘤中。与目前的间皮瘤标志物相比，SKM9-2 可以更特异性和更敏感地检测间皮瘤；因此，SKM9-2 可能有助于恶性间皮瘤的精确检测和诊断。在本研究中，我们研究了 SKM9-2 的表位。我们分析了 SKM9-2 与截断 HEG1 和候选表位融合糖基磷脂酰肌醇锚定蛋白的结合。SKM9-2 的表位被鉴定为 HEG1 中的 O-糖基化区域 893-SKSPSLVSLPT-903。表位的丙氨酸扫描分析表明，SKM9-2 结合到 HEG1 中的一个简单表位上，并且表位内的 SKxPSxVS 序列对于 SKM9-2 的识别是必需的。可溶性表位肽的质谱分析和凝集素结合分析表明，SKM9-2 表位中，丝氨酸未发生糖基化，包含两个二唾液酸化核心 1 O-连接糖修饰丝氨酸残基，Ser 和 Ser。神经氨酸酶处理分析也证实了间皮瘤细胞中的表位含有类似的糖基化修饰。因此，通过识别 HEG1 特定区域中唾液酸化糖修饰，SKM9-2 可以特异性检测间皮瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/5965314bdc0e/41598_2018_32534_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/eefa71c17b41/41598_2018_32534_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/5b6762b6b3ae/41598_2018_32534_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/1e9d4c189f6e/41598_2018_32534_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/418fade2ec9b/41598_2018_32534_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/78719dcab372/41598_2018_32534_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/1bf3fd1284b2/41598_2018_32534_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/fc2187fb70f0/41598_2018_32534_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/5965314bdc0e/41598_2018_32534_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/eefa71c17b41/41598_2018_32534_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/5b6762b6b3ae/41598_2018_32534_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/1e9d4c189f6e/41598_2018_32534_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/418fade2ec9b/41598_2018_32534_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/78719dcab372/41598_2018_32534_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/1bf3fd1284b2/41598_2018_32534_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/fc2187fb70f0/41598_2018_32534_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e67/6155162/5965314bdc0e/41598_2018_32534_Fig8_HTML.jpg

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