Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres

Abstract

<jats:p>Survivin, a subunit of the chromosome passenger complex (CPC), binds the N-terminal tail of histone H3, which is phosphorylated on T3 by Haspin kinase, and localizes the complex to the inner centromeres. We used x-ray crystallography to determine the residues of Survivin that are important in binding phosphomodified histone H3. Mutation of amino acids that interact with the histone N-terminus lowered in vitro tail binding affinity and reduced CPC recruitment to the inner centromere in cells, validating our solved structures. Phylogenetic analysis shows that nonmammalian vertebrates have two Survivin paralogues, which we name class A and B. A distinguishing feature of these paralogues is an H-to-R change in an amino acid that interacts with the histone T3 phosphate. The binding to histone tails of the human class A paralogue, which has a histidine at this position, is sensitive to changes around physiological pH, whereas Xenopus Survivin class B is less so. Our data demonstrate that Survivin paralogues have different characteristics of phosphospecific binding to threonine-3 of histone H3, providing new insight into the biology of the inner centromere.</jats:p>

Phosphorylation of threonine 3 on histone H3 by Haspin kinase is required for meiosis I in mouse oocytes

“…In mitosis, survivin detects the H3pT3 mark and is responsible for docking the complex at kinetochores (Kelly et al, 2010;Niedzialkowska et al, 2012). Similar to AURKC, we observed loss of survivin along the ICA, but retention at kinetochores (Fig.…”

A Centromere-Signaling Network Underlies the Coordination among Mitotic Events

“…Haspin kinase phosphorylates histone H3 on T3 during mitosis [26–28, 34]. The Survivin subunit of the CPC directly binds H3-pT3 to recruit the CPC to the inner-centromere (Figure 3A) [26–28,35]. The CPC in turn can stimulate haspin recruitment through phosphorylation, generating a positive feedback loop [36].…”

“…The bulk of cohesin is removed from chromatin during prophase by phosphorylation by mitotic kinases including CDK1, Plk1 and the CPC kinase Aurora B [54,55], and since the sisters remained cohesed along the central axis of chromosomes it is reasonable the cohesin remains high in this location (Figure 3D) [56]. The maintenance of cohesion in the central axis engages the cohesion loop of the CSN to spatially locate H3pT3 and the CPC to the central zone between the two sisters [26–28,35,40]. …”

A mathematical model of Aurora B activity in prophase and metaphase

“…01 s −1 [86] . A number of studies of CPC components binding with histones and with DNA [87][88][89] have measured dissociation constants, k u / k b , of about 1 μM. Therefore, we assume a value of 0 .…”