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

The 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.The 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.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[1,3-5]. The furin cleavage of the precursor protein yields two proteins, the N-terminal megakaryocyte potentiating factor (MPF), which is a soluble extra-cellular protein, and the C-terminal 327-residue mesothelin, which is membrane-bound by means of a glycosylphosphatidylinositol (GPI) anchor at the C-terminus of the protein [6]. The sequence of the human mesothelin (from NCBI accession number: NP_005814) is given in Figure 1, which also shows the furin cleavage site and the predicted GPI anchor site. Mesothelin and MPF are useful tumor markers [7,8]. Mesothelin is the target protein of an immunotoxin-based therapy of mesoth