Analyzing aggregation propensities of clinically relevant PTEN mutants: a new culprit in pathogenesis of cancer and other PTENopathies

Abstract

While studies on pathological protein aggregation are largely limited to neurodegenerative disease, emerging evidence suggests that other diseases are also associated with pathogenic protein aggregation. For example, tumor suppressor protein p53, and its mutant conformers, undergo protein aggregation, exacerbating the cancer phenotype. These findings raise the possibility that inactivation of tumor suppressors via protein aggregation may participate in cancer and other disease pathologies. Since tumor suppressor protein PTEN has similar functions to p53, and is mutated in multiple diseases, we examined the aggregation propensity of PTEN wild-type and 1523 clinically relevant PTEN mutants. Applying computational tools to PTEN mutation databases revealed that PTEN wild-type protein can aggregate under physiological conditions, and 274 distinct PTEN mutants had increased aggregation propensity. To understand the mechanism underlying PTEN conformer aggregation, we analyzed the physicochemical properties of these 274 PTEN mutants and defined their aggregation potential. We conclude that increased aggregation propensity of select PTEN mutants may contribute to disease phenotypes. Our studies have built the foundation for interrogating the aggregation potential of these select mutants in cancers and in PTENopathies. Elucidating the pathogenic mechanisms associated with aggregation-prone PTEN conformers will aid in developing therapies that target PTEN-aggregates in multiple diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cancer
• PTENopathies
• protein aggregation
• PTEN
• p53

Acknowledgements

The authors thank Dr. Justin Gibbons for helping us to generate input files of PTEN mutant sequences derived from various databases for TANGO analysis.

Disclosure statement

The authors declare no conflict of interest.

Data availability

The data, output and analysis that support the findings of this study are openly available in Mendeley Data at reserved DOI:http://doi.org/10.17632/3dxhn32c78.2.