Structural elucidation of the mesothelin-mucin-16/CA125 interaction,Structure

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Structural elucidation of the mesothelin-mucin-16/CA125 interaction
Structure ( IF 4.4 ) Pub Date : 2024-05-03 , DOI: 10.1016/j.str.2024.04.011
Peter B Rupert ₁ , Matthew Buerger ₁ , Della J Friend ₁ , Roland K Strong ₁

Affiliation

Mesothelin (MSLN) is a cell-surface glycoprotein expressed at low levels on normal mesothelium but overexpressed in many cancers. Mesothelin has been implicated to play role/s in cell adhesion and multiple signaling pathways. Mucin-16/CA125 is an enormous cell-surface glycoprotein, also normally expressed on mesothelium and implicated in the progression and metastasis of several cancers, and directly binds mesothelin. However, the precise biological function/s of mesothelin and mucin-16/CA125 remain mysterious. We report protein engineering and recombinant production, qualitative and quantitative binding studies, and a crystal structure determination elucidating the molecular-level details governing recognition of mesothelin by mucin-16/CA125. The interface is small, consistent with the ∼micromolar binding constant and is free of glycan-mediated interactions. Sequence comparisons and modeling suggest that multiple mucin-16/CA125 modules can interact with mesothelin through comparable interactions, potentially generating a high degree of avidity at the cell surface to overcome the weak affinity, with implications for functioning and therapeutic interventions.

中文翻译：

间皮素-粘蛋白-16/CA125 相互作用的结构阐明

间皮素 (MSLN) 是一种细胞表面糖蛋白，在正常间皮细胞中低水平表达，但在许多癌症中过度表达。间皮素在细胞粘附和多种信号传导途径中发挥作用。 Mucin-16/CA125 是一种巨大的细胞表面糖蛋白，通常也在间皮上表达，与多种癌症的进展和转移有关，并直接与间皮素结合。然而，间皮素和 mucin-16/CA125 的精确生物学功能仍然是个谜。我们报告了蛋白质工程和重组生产、定性和定量结合研究以及晶体结构测定，阐明了控制 mucin-16/CA125 识别间皮素的分子水平细节。该界面很小，与~微摩尔结合常数一致，并且没有聚糖介导的相互作用。序列比较和建模表明，多个 mucin-16/CA125 模块可以通过类似的相互作用与间皮素相互作用，可能在细胞表面产生高度的亲和力以克服弱亲和力，从而对功能和治疗干预产生影响。

更新日期：2024-05-03

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