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

Our plain-English summary of Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeats, by B.K. Sathyanarayana, Y. Hahn, M.S. Patankar, et al (BMC Structural Biology, 2009).

The study

• Authors: B.K. Sathyanarayana, Y. Hahn, M.S. Patankar, I. Pastan, B. Lee
• Journal: BMC Structural Biology
• Published: 2009;9:1
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: 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 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.

Results: 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.

Conclusion: 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.

In plain English

This was a computer-based study. The authors used online prediction programs to estimate the likely three-dimensional shape of mesothelin, a protein found on normal mesothelium and highly expressed in mesotheliomas. They also examined its larger precursor protein and two related inner-ear proteins, stereocilin and otoancorin. No people, animals or asbestos exposures were studied. Sequence searches found human and mouse otoancorins and stereocilins as relatives of mesothelin, but no related protein of known structure. Prediction programs indicated that mesothelin is made mostly of helical segments. Several structure programs, including INHUB and I-TASSER, produced models with a coiled, repeating (superhelical) shape built from ARM-type repeats. For stereocilin, 15 of 18 hits were ARM repeat structures; for otoancorin, 8 of 10 were. Some other programs gave different results or none. The authors concluded that these proteins are predicted to share this structure, and they proposed that the proteins bind the carbohydrate (sugar) part of glycoproteins. They stated that their model suggests only the likely type of structure and that the real structure will differ.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Computational (bioinformatics) protein structure prediction study using sequence searches and secondary and three-dimensional structure prediction servers
• Who was studied: No human or animal subjects. Protein sequences were studied: human mesothelin (NCBI NP_005814) and its precursor, plus stereocilin (1775 residues) and otoancorin (1153 residues). Mesothelin is described as found in normal mesothelium and highly expressed in cancers including mesotheliomas.
• Exposure: None. No asbestos or other exposure was studied; the study concerned the predicted structure of proteins.
• Main results:
  • PSI-BLAST sequence searches found otoancorins and stereocilins from human and mouse as related proteins. There were no hits against the Protein Data Bank (proteins of known structure).
  • Secondary structure prediction programs predicted a predominantly helical structure for mesothelin and its precursor, and also for stereocilin and otoancorin.
  • For the mesothelin precursor, the 3D-Jury metaserver produced three hits, all superhelical structures with ARM repeats. It produced no hits for the mesothelin sequence alone.
  • For mesothelin alone, the highest scoring eight structures from the INHUB server were all ARM repeat proteins. The 3D-PSSM server gave no hits with E less than 1.0.
  • INHUB and I-TASSER produced models of mesothelin with superhelical structures and ARM-type repeats. All 10 I-TASSER models (5 for the precursor, 5 for mesothelin) had this type of structure.
  • Other structure prediction servers gave more varied results. The authors judged the FFAS predictions (Leucine-Rich Repeat structures) unlikely to be correct, and Paircoil2 predicted no coiled coil fold.
  • For stereocilin, 15 of a total 18 hits from 3D-PSSM (E less than 1.0) were ARM repeat superhelical structures.
  • For otoancorin, 8 of 10 hits from 3D-PSSM (E less than 1.0) were ARM repeat superhelical proteins.
  • The authors identified 108 proteins in the Protein Data Bank with ARM-type repeats, all of them intracellular.
• The authors' conclusion: The authors suggested that the mesothelin superfamily (mesothelin, megakaryocyte potentiating factor, mesothelin precursor, MPFL, stereocilin and otoancorin) has a superhelical structure made of ARM/HEAT-like repeats. They proposed that all these proteins function as lectins that bind the carbohydrate part of glycoproteins.
• Limitations the authors state:
  • The model is meant to suggest only the type of structure mesothelin is likely to have.
  • The real structure of mesothelin will inevitably differ from the model.
  • Some or all residues of the model's last repeat are presumably missing after the protein is attached to the cell membrane (GPI modification).
  • The N-terminal region of mesothelin may not follow the ARM-type repeat structure, because it includes a region predicted to be disordered.
  • The mesothelin sequence used for all calculations inadvertently carried two extra residues. The authors believed this would not significantly affect the results.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelial Cells, Mesothelioma, Adenocarcinoma, Ovarian Cancer, Metastasis, Glycoprotein.

Related studies

• Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution — D.S. Kim, Y. Hahn (2011)
• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma — J. Creaney, D. Yeoman, et al. (2008)
• Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma — K. Hollevoet, K. Nackaerts, et al. (2010)
• Diagnostic values of soluble mesothelin-related peptides for malignant pleural mesothelioma: updated meta-analysis — A. Cui, X.G. Jin, et al. (2014)
• Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin — K. Iwahori, T. Osaki, et al. (2008)

Browse return to medical research.