pseudokinase

A pseudokinase is a protein containing a kinase-like catalytic domain but lacking one or more residues essential for phosphotransfer, yielding absent or extremely low catalytic activity. Nevertheless, pseudokinases commonly regulate signaling by acting as scaffolds or allosteric modulators, coordinating interactions among kinases and substrates. They are widespread in eukaryotes and form a substantial part of the kinome.

Many pseudokinases can bind ATP or nucleotides without transferring phosphate, and this binding can influence conformation and interactions. Their roles include guiding localization, assembling signaling complexes, and modulating the activity and specificity of catalytically active kinases. In some cases, rare reactivation or residual activity has been reported but is not typical.

Conserved catalytic motifs are often altered in pseudokinases, for example substitutions at the lysine in subdomain II (VAIK), the HRD catalytic aspartate, or the DFG motif, which weaken or abolish catalysis. Despite these changes, the kinase fold often remains intact, enabling functional interactions with ATP, substrates, and partners.

Prominent examples include HER3 (ERBB3), a receptor tyrosine kinase family member that binds ATP but is catalytically impaired; STRADα/β, which regulate the LKB1 complex; MLKL, an effector of necroptosis; BUBR1, part of the spindle checkpoint; and the tribbles proteins TRIB1-TRIB3, which act as scaffolds in MAPK signaling and ubiquitin-mediated regulation.

Pseudokinases are of interest in research and medicine for their regulatory roles and potential as therapeutic targets. Because they lack catalytic activity, strategies focus on disrupting protein interactions or allosteric regulation rather than inhibiting phosphotransfer.