Kinases on Double Duty: A Review of UniProtKB Annotated Bifunctionality within the Kinome

Abstract

Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity. We searched the Universal Protein Resource Knowledgebase (UniProtKB) database for bifunctional protein kinases and focused on kinases that are critical for bacterial and human cellular homeostasis. These kinases engage in diverse functional roles, ranging from environmental sensing and metabolic regulation to immune-host defense and cell cycle control. Herein, we describe their dual catalytic activities and how they contribute to disease pathogenesis.

Keywords: cancer; inflammation; kinase; metabolism; phosphorylation; signal transduction.

Figure 1

Domain architecture of bifunctional kinases. Representative structural domain schematic of 22 unique bifunctional kinases annotated in the UniProtKB database. Abbreviations denote the following: kinase domain (KD), Ras-binding domain (RBD), adaptor-binding domain (ABD), Cys-His-Lys homology domain (CHK), chaperonin-60–T-complex protein 1 subunit alpha domain (Cpn60-TCP1), disheveled–EGL10–pleckstrin domain (DEP), Fab 1–YOTB–Vac 1–EEA1 zinc finger domain (FYVE), endoribonuclease (RNase), luminal domain (LD), double-stranded RNA binding domain (dsRBD), C-terminal kinase domain (CTKD), N-terminal kinase domain (NTKD), TATA-box binding protein (TBP), histone acetyltransferase domain (HAT), bromodomain (bromo), leucine-rich repeat (LRR), GTP-binding domain (GTP), Pro-Ser-Thr rich domain (P/S/T), acidic domain (AD), β-transducin repeat (WD40), C-terminal of Roc domain (COR), Ras of complex G-domain (Roc), ankyrin domain (Ank), Armadillo domain (Arm), kinase-associated 1 domain (KA1), TP dipeptide-rich domain (TP rich), ubiquitin-associated region (UBA), Mig6 homology region (MHR), PPXY motif (P), clathrin-interacting region (CL), Cdc42/GTPase binding domain (C), Src homology 3 domain (SH3), sterile alpha motif (SAM), caspase activation/recruitment domain (CARD), N-terminal domain (NTD), kinase and phosphatase/phosphorylase/pyrophosphorylase domain (KD/PPase), Per-Arnt-Sim domain (PAS), PP2C-like phosphatase domain (PP2C).