Enzymatic Function of an Intrinsically Disordered Protein

Abstract Intrinsically disordered proteins (IDPs) challenge the traditional structure-function paradigm by lacking a stable three-dimensional structure 1 . While their roles as dynamic effectors, scaffolds, and molecular switches are well-established, it has been widely accepted that enzymatic activity requires a stably folded catalytic center 2 . Here, we challenge this dogma by demonstrating that a 284-amino acid intrinsically disordered domain of the cytoskeleton-associated protein 2 (CKAP2) is sufficient to catalyze both microtubule polymerization and depolymerization. CKAP2 promotes tubulin incorporation without high-affinity tubulin binding, suggesting a transition-state-based catalytic mechanism distinct from known microtubule polymerases. These findings establish, for the first time, that an intrinsically disordered domain can function as a bona fide enzyme, expanding our understanding of the functional repertoire of disordered proteins and their roles in cellular processes.