dominantnegative

Dominant negative, or dominant-negative mutation, describes a mutant gene product that interferes with the function of the normal, wild-type product. The effect is often observed in proteins that form multimers or require assembly with other subunits. The term antimorph is sometimes used for this phenomenon.

Mechanism: The mutant protein can bind to substrates, DNA, or partner proteins but disrupts complex formation or activity. By forming nonfunctional hetero-oligomers, sequestering cofactors, or competing for binding sites, it reduces overall activity even when the wild-type allele is present. The strength of the effect depends on expression and stoichiometry.

Examples: A well-known case is p53, in which dominant-negative mutants form mixed tetramers with wild-type p53 and inhibit transcriptional activation. Other instances include dominant-negative versions of dimerizing transcription factors and decoy kinase-dead receptor mutants that block signaling when coexpressed with functional proteins.

Applications and implications: Researchers use dominant-negative constructs to study gene function and pathway relationships. Clinically, they have been explored as therapeutic tools to blunt harmful signaling, but delivery, specificity, and safety are major hurdles. Naturally occurring dominant negatives can contribute to disease by reducing normal protein activity.

Limitations: The effect depends on relative abundance of mutant and wild-type protein, stability of the mutant, and the architecture of the target complex. Not all proteins are susceptible to dominant-negative inhibition, and off-target effects or compensation by related proteins can occur.