Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeats

Bangalore K Sathyanarayana,Ira Pastan,Yoonsoo Hahn,Manish S Patankar,Byungkook Lee

doi:10.1186/1472-6807-9-1

Abstract

BackgroundMesothelin is a 40 kDa protein present on the surface of normal mesothelial cells and overexpressed in many human tumours, including mesothelioma and ovarian and pancreatic adenocarcinoma. It forms a strong and specific complex with MUC16, which is also highly expressed on the surface of mesothelioma and ovarian cancer cells. This binding has been suggested to be the basis of ovarian cancer metastasis. Knowledge of the structure of this protein will be useful, for example, in building a structural model of the MUC16-mesothelin complex. Mesothelin is produced as a precursor, which is cleaved by furin to produce the N-terminal half, which is called the megakaryocyte potentiating factor (MPF), and the C-terminal half, which is mesothelin. Little is known about the function of mesothelin and there is no information on its possible three-dimensional structure. Mesothelin has been reported to be homologous to the deafness-related inner ear proteins otoancorin and stereocilin, for neither of which the three-dimensional structure is known.ResultsThe BLAST and PSI-BLAST searches confirmed that mesothelin and mesothelin precursor proteins are remotely homologous to stereocilin and otoancorin and more closely homologous to the hypothetical protein MPFL (MPF-like). Secondary structure prediction servers predicted a predominantly helical structure for both mesothelin and mesothelin precursor proteins and also for stereocilin and otoancorin. Three-dimensional structure prediction servers INHUB and I-TASSER produced structural models for mesothelin, which consisted of superhelical structures with ARM-type repeats in conformity with the secondary structure predictions. Similar ARM-type superhelical repeat structures were predicted by 3D-PSSM server for mesothelin precursor and for stereocilin and otoancorin proteins.ConclusionThe mesothelin superfamily of proteins, which includes mesothelin, mesothelin precursor, megakaryocyte potentiating factor, MPFL, stereocilin and otoancorin, are predicted to have superhelical structures with ARM-type repeats. We suggest that all of these function as superhelical lectins to bind the carbohydrate moieties of extracellular glycoproteins.

Highlights

Mesothelin is a 40 kDa protein present on the surface of normal mesothelial cells and overexpressed in many human tumours, including mesothelioma and ovarian and pancreatic adenocarcinoma
We suggest that all three proteins – mesothelin, otoancorin and stereocilin – function as superhelical lectins that bind the extracellular glycoprotein matrix to the surface of the cell to which they are anchored
There were no hits from BLAST or PSI-BLAST against Protein Data Bank (PDB) [20] for any of the three proteins mesothelin, stereocilin or otoancorin

Summary

Introduction

Mesothelin is a 40 kDa protein present on the surface of normal mesothelial cells and overexpressed in many human tumours, including mesothelioma and ovarian and pancreatic adenocarcinoma. It forms a strong and specific complex with MUC16, which is highly expressed on the surface of mesothelioma and ovarian cancer cells. Mesothelin is a cell surface protein that is found in normal mesothelium and highly expressed in several cancers including mesotheliomas and ovarian and pancreatic cancers[1,2] It is produced as a part of the 69 kDa precursor protein[1,3,4,5]. Mesothelin is the target protein of an immunotoxin-based therapy of mesotheliomas and ovarian and pancreatic cancers, of which the phase I clinical trial has been completed [9]

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