Structural conservation and divergence across the Receptor Tyrosine Kinase superfamily

Fassler Bakhman, A.; Kolodny, R.; Kosloff, M.

doi:10.1101/2024.12.31.630944

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bioRxiv · 10.1101/2024.12.31.630944

Structural conservation and divergence across the Receptor Tyrosine Kinase superfamily

Fassler Bakhman, A.·Kolodny, R.·Kosloff, M.

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Abstract

Members of the Receptor Tyrosine Kinase (RTK) superfamily are regulators of cellular signaling, playing essential roles in cellular growth, differentiation, and survival. Dysregulation of RTKs leads to diseases such as cancer, diabetes, and inflammatory disorders, making them important therapeutic targets. Despite extensive research on RTKs, the structural diversity and evolutionary relationships across the superfamily are not fully understood. Here, we systematically compared structural conservation and divergence among 245 extracellular domains from 54 RTKs, across 18 RTK families. Using experimentally-resolved structures and AlphaFold2 models, we conducted an all-versus-all structural alignment to explore domain architecture and quantify significant structural similarities within the RTK superfamily. We curated a comprehensive database encompassing PDB structures, 3D folds, ligand-binding properties, and sequence information of all RTK domains analyzed (https://fasslero.github.io/RTK-domains). Our analysis revealed numerous inter-family similarities and remote evolutionary connections, in particular among ligand-binding domains (LBDs), and distinct structural domain types and unexpected dissimilarities among domains previously classified as related. Our work highlights the intricate balance between structural conservation and divergence in RTKs and sheds light on the evolutionary mechanisms shaping this critical superfamily.

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Fassler Bakhman, A., Kolodny, R., Kosloff, M.. 2025-01-02. Structural conservation and divergence across the Receptor Tyrosine Kinase superfamily. https://doi.org/10.1101/2024.12.31.630944

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