| INCENP (inner centromere protein) is a core scaffold of the chromosomal passenger complex (CPC) that coordinates chromosome segregation, error correction, and cytokinesis by physically coupling Aurora B kinase to centromeric chromatin and spindle microtubules throughout mitosis. The N-terminal region of INCENP forms a parallel three-helix bundle with Survivin and Borealin, creating the CPC localization module that targets the complex first broadly along chromosome arms, then to inner centromeres at metaphase and finally to the spindle midzone and midbody during anaphase and telophase, while the C-terminal IN-box element wraps around the small lobe of Aurora B and provides the primary activation interface for the catalytic subunit. Human Aurora B bound to the INCENP IN-box shows that INCENP allosterically stabilizes an active-like T-loop conformation, opens the catalytic cleft, and positions key residues in the active site, and that subsequent phosphorylation of two serines in the INCENP C-terminus further shifts the complex into a fully active kinase state, establishing a two-step mechanism in which INCENP first primes and then, when phosphorylated, maximally activates Aurora B. INCENP and Aurora B are mutually dependent: INCENP is required to localize Aurora B correctly and to support its histone H3 Ser10 kinase activity, whereas Aurora B is needed for INCENP accumulation at centromeres and transfer to the spindle at anaphase, and depletion of either component leads to severe defects in histone H3 phosphorylation, metaphase chromosome alignment, sister kinetochore disjunction, and completion of cytokinesis, without completely blocking anaphase onset. INCENP’s central intrinsically disordered region acts as a flexible “dog-leash” that links the centromere-bound CPC core to kinetochore and microtubule substrates; phosphorylation within this disordered segment tunes its elongation and cohesiveness, modulating the reach and dynamic sampling of Aurora B across the inner centromere–kinetochore axis and thereby influencing tension sensing and the spatial error-correction gradient that destabilizes incorrect microtubule–kinetochore attachments. Ablation of INCENP in mitotic cells disrupts recruitment of Aurora B to centromeres, impairs spindle checkpoint signaling, allows cells to exit mitosis with misaligned or lagging chromosomes, and causes frequent cytokinesis failure, all of which contribute to chromosomal instability; in meiosis, INCENP and Aurora B are additionally required for centromeric localization of the shugoshin MEI-S332 and maintenance of sister chromatid cohesion, linking CPC activity to specialized meiotic centromere behavior. Overexpression of INCENP in colorectal and other tumor cell lines, where it colocalizes with Aurora B on metaphase chromosomes and midbodies, and co-overexpression of Aurora B and INCENP in model systems can profoundly disrupt chromosome segregation, consistent with a role for altered CPC stoichiometry in tumor-associated aneuploidy and in modulating sensitivity to Aurora B inhibitors. Across these contexts, INCENP functions as a modular CPC organizer and Aurora B activator whose structured N- and C-terminal domains and phosphorylation-regulated disordered linker together define where and how Aurora B acts on chromatin and microtubule substrates. |
