Structure of a Survivin–Borealin–INCENP Core Complex Reveals How Chromosomal Passengers Travel Together

Abstract

The chromosomal passenger complex (CPC) is a key regulator of chromosome segregation and cytokinesis. CPC functions are connected to its localization. The complex first localizes to centromeres and later associates with the central spindle and midbody. Survivin, Borealin, and INCENP are the three components of the CPC that regulate the activity and localization of its enzymatic component, the kinase Aurora B. We determined the 1.4 A resolution crystal structure of the regulatory core of the CPC, revealing that Borealin and INCENP associate with the helical domain of Survivin to form a tight three-helical bundle. We used siRNA rescue experiments with structure-based mutants to explore the requirements for CPC localization. We show that the intertwined structural interactions of the core components lead to functional interdependence. Association of the core "passenger" proteins creates a single structural unit, whose composite molecular surface presents conserved residues essential for central spindle and midbody localization.

Cytokinesis and cancer

“…Microtubule-associated proteins PRC1 [13,14] Centralspindlin complex CYK-4 [2,15] MKLP1 [2,15] Chromosome passenger complex INCENP [16,17] Survinin [16,17] Borealin [16,17] Aurora B [16,17] ESRCTs and associated proteins CEP55 [30][31][32] TSG101 [31,32] ALIX [31,32] CHMP1B [33] Spastin [33] CHMP4B [31,32,34] FYVE-CENT [34] TTC19 [34] Kinesins KIF4A [14] MKLP2 [17] MPP1 [22] KIF14 [23] KIF13A [34] Additional proteins NuSAP [18] Orbit [19] ASP [20] TBCD [21] ECT2 [24] FIP3 [25] PLK1 [26,27] Septins [28] Anillin [29] during anaphase and cytokinesis and is important for the last step of abscission. CEP55 binds directly MKLP1 and is controlled by centralspindlin, since knockdown of centralspindlin abolishes CEP55 from the midbody [30].…”

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

“…Survivin is a chromosomal passenger protein 22 and interacts with other proteins in the chromosomal passenger complex, such as aurora kinase B, inner centromere protein, and borealin. 23 Signal transducer and activator of transcription 3 (STAT3) and p53 proteins regulate survivin expression. 24,25 Cyclin-dependent kinase1 and heat shock protein 90 participate in posttranslational modifications of survivin by regulating survivin's stability.…”

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

“…The N-terminal region of Borealin encodes an extended helix which interacts with both Survivin and INCENP to form a three-helix bundle ( Figure 4C; Jeyaprakash et al, 2007). The Phyre-based model of Nbl1 (N29-H83) is consistent with core features of Borealin important for this interaction, containing both an extended coiled-coil followed by a helical region similar to the region of Borealin which binds to the dimerization arm of Survivin ( Figure 4C).…”

“…The first match was the N terminus of human Borealin, with an E value of 0.35 and estimated precision of 85% (PDB ϭ 2RAX, Bourhis et al, 2007). All other matches were unrelated helical proteins with significantly lower similarity (E value Ͼ2.7, precision Ͻ55%).The N-terminal region of Borealin encodes an extended helix which interacts with both Survivin and INCENP to form a three-helix bundle ( Figure 4C; Jeyaprakash et al, 2007). The Phyre-based model of Nbl1 (N29-H83) is consistent with core features of Borealin important for this interaction, containing both an extended coiled-coil followed by a helical region similar to the region of Borealin which binds to the dimerization arm of Survivin ( Figure 4C).…”