1. Structural elucidation of the mesothelin-mucin-16/CA125 interaction.
- Author
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Rupert PB, Buerger M, Friend DJ, and Strong RK
- Subjects
- Humans, Crystallography, X-Ray, Binding Sites, Recombinant Proteins metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Amino Acid Sequence, Protein Engineering, Membrane Proteins, Mesothelin metabolism, CA-125 Antigen metabolism, CA-125 Antigen chemistry, Protein Binding, GPI-Linked Proteins metabolism, GPI-Linked Proteins chemistry, GPI-Linked Proteins genetics, Models, Molecular
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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