- Pseudokinases are protein domains that share significant structural similarity with protein kinases but lack key catalytic residues required for phosphoryl transfer. These proteins were initially considered “dead” kinases, but research has revealed their crucial roles as sophisticated signaling molecules.
- The structure of pseudokinases maintains the characteristic bilobal fold of typical protein kinases, consisting of an N-terminal lobe rich in β-sheets and a larger C-terminal lobe dominated by α-helices. However, they lack one or more of the three essential motifs required for catalysis: the VAIK motif (which positions ATP), the HRD motif (which acts as a catalytic base), or the DFG motif (which coordinates magnesium ions).
- Despite their inability to catalyze phosphoryl transfer, pseudokinases have evolved to perform diverse cellular functions. They often act as allosteric regulators, molecular switches, or scaffolding proteins that coordinate the assembly of signaling complexes. Some pseudokinases can bind nucleotides or substrate proteins, using these interactions to modulate their biological functions without catalyzing phosphorylation.
- Pseudokinases comprise approximately 10% of the human kinome, and their importance is highlighted by their involvement in various diseases. Mutations in pseudokinases have been linked to cancer, developmental disorders, and inflammatory conditions. For example, the pseudokinase MLKL plays a crucial role in necroptosis, a form of programmed cell death, while HER3/ERBB3 is an important regulator of cancer cell signaling.
- Research has shown that some pseudokinases retain vestigial catalytic activity or can be reactivated under specific conditions. This suggests that the boundary between kinases and pseudokinases may be more fluid than initially thought. Understanding these proteins’ evolution provides insights into how nature repurposes protein domains for new functions.
- Recent technological advances, including structural biology techniques and protein engineering approaches, have enhanced our understanding of pseudokinase mechanisms. This knowledge has led to the development of therapeutic strategies targeting pseudokinases in various diseases, demonstrating their potential as drug targets despite their lack of conventional enzymatic activity.
Reliability Index *****
Note: If you notice any errors or inconsistencies, we welcome your feedback. Please share your observations in the comment box below — your input helps us improve.
Highest reliability: *****
Lowest reliability: *****
