MAST Kinases' Function and Regulation: Insights from Structural Modeling and Disease Mutations.

Area of Science:

• Evolutionary biology
• Structural biology
• Bioinformatics

Background:

• MAST kinases are ancient AGC kinases implicated in human diseases including cancer, diabetes, and neurodevelopmental disorders.
• Understanding MAST kinase origins and diversification is crucial for future research and therapeutic development.

Purpose of the Study:

• To elucidate the evolutionary origins and diversification of MAST kinases using structural and bioinformatic approaches.
• To predict the functional impact of disease-associated mutations on MAST protein stability.

Main Methods:

• Sequence and database analysis of MAST-lineage kinases across various organisms.
• Integration of predictive algorithms and AlphaFold for estimating mutation effects on protein stability.

Main Results:

• Higher organisms possess multiple MAST kinases and a single MASTL kinase, all conserving AGC kinase, DUF1908, and PDZ domains.
• Early MAST-like proteins in *D. discoideum* and plants show domain loss, while mammalian MAST1-4 exhibit tissue-specific expression and likely 14-3-3 regulation.
• In silico analysis predicted that specific mutations (e.g., MAST1-L232P, G522E) likely destabilize MAST proteins.

Conclusions:

• MAST and MASTL kinases evolved from a common primordial MAST ancestor, with subsequent expansion and diversification in mammals.
• Mammalian MAST kinases are likely regulated by 14-3-3 proteins, and pathogenic mutations often affect post-translational modification sites within DUF and kinase domains.
• This study provides a computational framework for investigating MAST kinase regulation and developing novel drug discovery strategies.