Abstract
BackgroundProtein kinases are among the largest druggable family of signaling proteins, involved in various human diseases, including cancers and neurodegenerative disorders. Despite their clinical relevance, nearly 30% of the 545 human protein kinases remain highly understudied. Comparative genomics is a powerful approach for predicting and investigating the functions of understudied kinases. However, an incomplete knowledge of kinase orthologs across fully sequenced kinomes severely limits the application of comparative genomics approaches for illuminating understudied kinases. Here, we introduce KinOrtho, a query- and graph-based orthology inference method that combines full-length and domain-based approaches to map one-to-one kinase orthologs across 17 thousand species.ResultsUsing multiple metrics, we show that KinOrtho performed better than existing methods in identifying kinase orthologs across evolutionarily divergent species and eliminated potential false positives by flagging sequences without a proper kinase domain for further evaluation. We demonstrate the advantage of using domain-based approaches for identifying domain fusion events, highlighting a case between an understudied serine/threonine kinase TAOK1 and a metabolic kinase PIK3C2A with high co-expression in human cells. We also identify evolutionary fission events involving the understudied OBSCN kinase domains, further highlighting the value of domain-based orthology inference approaches. Using KinOrtho-defined orthologs, Gene Ontology annotations, and machine learning, we propose putative biological functions of several understudied kinases, including the role of TP53RK in cell cycle checkpoint(s), the involvement of TSSK3 and TSSK6 in acrosomal vesicle localization, and potential functions for the ULK4 pseudokinase in neuronal development.ConclusionsIn sum, KinOrtho presents a novel query-based tool to identify one-to-one orthologous relationships across thousands of proteomes that can be applied to any protein family of interest. We exploit KinOrtho here to identify kinase orthologs and show that its well-curated kinome ortholog set can serve as a valuable resource for illuminating understudied kinases, and the KinOrtho framework can be extended to any protein-family of interest.
Highlights
Protein kinases are among the largest druggable family of signaling pro‐ teins, involved in various human diseases, including cancers and neurodegenerative disorders
A major focus of the Illuminating the Druggable Genome (IDG; https://commonfund.nih.gov/idg/index) consortium is to characterize the functions of these understudied proteins as a conceptual starting point for developing new drugs for a wide range of diseases such as cancer, neurodegenerative and autoimmune disorders that are associated with abnormal kinome signaling [19]
Traditional orthology inference methods start from an all-vs-all homology search, which would require orders of magnitude pairwise sequence comparisons for this sample of reference proteomes
Summary
Protein kinases are among the largest druggable family of signaling pro‐ teins, involved in various human diseases, including cancers and neurodegenerative disorders Despite their clinical relevance, nearly 30% of the 545 human protein kinases remain highly understudied. A majority of the human kinome members have been functionally characterized in multiple model organisms; nearly 30% of human kinases remain understudied, despite multi-organism knowledge of their primary sequence [11,12,13] These are collectively referred to as “dark” kinases based on a subset of metrics such as the number of published papers (Jensen PubMed score [14] < 50 and PubTator score [15] < 150) and grant funding (no R01). A major focus of the Illuminating the Druggable Genome (IDG; https://commonfund.nih.gov/idg/index) consortium is to characterize the functions of these understudied proteins as a conceptual starting point for developing new drugs for a wide range of diseases such as cancer, neurodegenerative and autoimmune disorders that are associated with abnormal kinome signaling [19]
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