Kinetochore-microtubule coupling mechanisms mediated by the Ska1 complex and Cdt1

Abstract

The faithful segregation of duplicated sister chromatids rely on the remarkable ability of kinetochores to sustain stable load bearing attachments with the dynamic plus ends of kinetochore-microtubules (kMTs). The outer layer of the kinetochore recruits several motor and non-motor microtubule-associated proteins (MAPs) that help the kinetochores establish and maintain a load bearing dynamic attachment with kMTs. The primary kMT-binding protein, the Ndc80 complex (Ndc80c), which is highly conserved among diverse organisms from yeast to humans, performs this essential function with assistance from other MAPs. These MAPs are not an integral part of the kinetochore, but they localize to the kinetochore periodically throughout mitosis and regulate the strength of the kinetochore microtubule attachments. Here, we attempt to summarize the recent advances that have been made toward furthering our understanding of this co-operation between the Ndc80c and these MAPs, focusing on the spindle and kinetochore-associated 1 (Ska1) complex (Ska1c) and Cdc10-dependent transcript 1 (Cdt1) in humans.

Keywords: Chromosomes; Kinetochores; MAPs; Microtubules; Mitosis; Ndc80.

Figure 1.. Mechanisms of kinetochore-microtubule coupling in Yeast (1A) and Humans (1B) as summarized in this review.

Each model is distinguished by the microtubule‐associated proteins (MAPs) assisting the Ndc80c in the kMT coupling process (1A and 1B). Regions of interaction relevant for each MAP to localize to kinetochores by binding to Ndc80c is also depicted. Proteins or protein complexes are drawn in arbitrary shapes for the purpose of depiction only and are not to a precise scale. The Dam1 ring complex in yeast binds to MT lattice/plus-ends and localizes to the kinetochore via multiple interactions with Ndc80c as described in the main manuscript (1A). Binding of the human Ska1c to kinetochores is also thought to require multiple interaction with the Ndc80c, including those with the loop domain, again, as outlined in the manuscript (1B). As with the Dam1c, Ska1c has been shown to bind both to the MT lattice and to the plus-ends. Human Cdt1 binds MTs directly and its recruitment to kinetochores is dependent on the loop domain of the Ndc80c (1B). The Mis12 complex and the proteins of the CCAN including CENP-C and CENP-T, which are important to localize the Ndc80c to outer kinetochores are indicated with the same colour in both models. These models are not meant to depict that the Ndc80c recruited to kinetochores via a particular component of CCAN (i.e. CENP-C or CENP-T) exhibit any sort of preference for binding to Ska1c or Cdt1. Any such representation is solely meant for the purpose of ease in illustration.

Figure 2.. Structural comparison of Cdt1 and SKA1 subunit of the Ska1c.

Linear and topology diagram of the canonical WTH domains (shown in orange within the grey area). α and β represent α helix and β sheet structures respectively. Note that Cdt1 (to the left, 2A) contain two WTHs: C-terminal WTH (WHC) is shown under the solid box and the middle WTH (WHM) is shown under the dotted box. In addition to the canonical WTH topology possessed by the WHM of Cdt1, the WHC contains one additional α helical component (α4). The single WTH domain of SKA1 (to the right, 2B) has 5 additional helical elements organized as two separate modules (I and II) as indicated. Secondary structural units that are unique to Cdt1 and SKA1 are shown in green.