Molecular Basis for CPC-Sgo1 Interaction: Implications for Centromere Localisation and Function of the CPC

Abstract

The Chromosomal Passenger Complex (CPC; consisting of Borealin, Survivin, INCENP and Aurora B kinase) and Shugoshin 1 (Sgo1) are key regulators of chromosome bi-orientation, a process essential for error-free chromosome segregation. Their functions rely on their ability to associate with centromeres. Two histone phosphorylations, histone H3 Thr3 (H3T3ph; directly recognised by Survivin) and histone H2A Thr120 (H2AT120ph; indirectly recognised via Sgo1), together with CPC′s intrinsic ability to bind nucleosome, facilitate CPC centromere recruitment. The molecular basis for CPC-Sgo1 binding and how their direct interaction influences CPC centromere localisation and function are lacking. Here, using an integrative structure-function approach, we show that the histone H3-like Sgo1 N-terminal tail interacts with Survivin acting as a hot-spot for CPC-Sgo1 assembly, while downstream Sgo1 residues, mainly with Borealin contributes for high affinity interaction. Disruption of the Sgo1 N-terminal tail-Survivin interaction abolished CPC-Sgo1 assembly in vitro and perturbed centromere localisation and function of CPC. Our findings provide evidence that CPC binding to Sgo1 and histone H3 N-terminal tail are mutually exclusive, suggesting that these interactions will likely take place in a spatially/temporally restricted manner and provide a rationale for the Sgo1-mediated ′kinetochore proximal centromere pool′ of CPC.

The Role of Mitotic Kinases and the RZZ Complex in Kinetochore-Microtubule Attachments: Doing the Right Link

“…It has been recently proposed that such well-confined concentration of CPC molecules may be important for the precise regulation of SAC signaling (Liang et al, 2020), although another study diverges on this matter (Hadders, 2020). On the other hand, in higher eukaryotes, the maintenance of normal levels of centromeric AURORA B is regarded as crucial to regulate KT-MT error correction and prevent chromosome mis-segregation Hadders, 2020;Liang et al, 2020;Abad et al, 2021). Whether each CPC pool controls specific players involved in error correction, as suggested by the ability of individual phospho-histone marks to ensure faithful chromosome segregation, remains to be determined.…”

Molecular convergence by differential domain acquisition is a hallmark of chromosomal passenger complex evolution

“…On the other hand, Survivin binds via its Baculovirus IAP Repeat (BIR) domain to phosphorylated threonine 3 in the tail of histone H3 (H3T3 ph ) that becomes phosphorylated by the kinase Haspin ( 10 – 12 ). In addition, a recent study showed that Survivin is also able to bind Shugoshin at its N terminus, which structurally resembles the phosphorylated H3 tail ( 13 ). Since both interactions involve the same site of Survivin’s BIR domain, they are considered mutually exclusive in accordance with the model of two spatially distinct CPC pools: a Bub1-dependent kinetochore-proximal centromere pool, involving interactions of Survivin and Borealin with Shugoshin, and a Haspin-dependent inner centromere pool entailing the H3T3 ph Survivin contact ( 14 – 16 ).…”