8VM1

Structural Elucidation of the Mesothelin Mucin16 CA125 Interaction

Summary for 8VM1

• Entry DOI: 10.2210/pdb8vm1/pdb
• Descriptor: Mesothelin, cleaved form,Mucin-16, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: linked complex, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 22908.95

Authors

Rupert, P.B.,Strong, R. (deposition date: 2024-01-12, release date: 2024-09-04, Last modification date: 2024-10-16)

Primary citation

Rupert, P.B.,Buerger, M.,Friend, D.J.,Strong, R.K.
Structural elucidation of the mesothelin-mucin-16/CA125 interaction.
Structure, 32:1049-1054.e2, 2024

PubMed 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.

PubMed: 38703776
DOI: 10.1016/j.str.2024.04.011

Experimental method

X-RAY DIFFRACTION (2.65 Å)