Emerging Insights into the Function of Kinesin-8 Proteins in Microtubule Length Regulation

Abstract

Proper regulation of microtubules (MTs) is critical for the execution of diverse cellular processes, including mitotic spindle assembly and chromosome segregation. There are a multitude of cellular factors that regulate the dynamicity of MTs and play critical roles in mitosis. Members of the Kinesin-8 family of motor proteins act as MT-destabilizing factors to control MT length in a spatially and temporally regulated manner. In this review, we focus on recent advances in our understanding of the structure and function of the Kinesin-8 motor domain, and the emerging contributions of the C-terminal tail of Kinesin-8 proteins to regulate motor activity and localization.

Keywords: microtubule dynamics; mitosis; molecular motor protein; spindle.

Figure 1

Proposed models for Kinesin-8 MT) depolymerization: (A) The active depolymerization model proposes that the Kinesin-8 motor protein walks on the MT lattice towards the plus end where it dwells for some time before depolymerizing the MT. (B) The capping model proposes that the Kinesin-8 protein, particularly human Kif18A, suppresses MT dynamics at the plus ends by serving as a capping factor. Capping blocks both growth and shrinkage, ultimately leading to MT catastrophe and depolymerization of the MT lattice.

Figure 2

Crystal structures of Kinesin-8 proteins and their cryo-EM MT docked state: (A) Undocked Kif18A complexed with Mg²⁺-ADP (PDB: 3LRE) [82]. (B) Nucleotide free Kif18A docked to the MT (PDB: 5OAM) [77]. (C) Undocked Kif19A complexed with Mg²⁺-ADP (PDB: 5GSZ) [79]. (D) Nucleotide free Kif19A docked to the MT (PDB: 5GSY; tubulin coordinates provided by N. Hirokawa) [79]. Key elements required for MT binding and/or MT destabilizing activity are color coded: Switch II cluster (α4-L12-α5) is shown in green, loop L2 in blue, helix α6 in orange, loop L11 in cyan, loop L8 in red, and neck linker (NL) in purple. Helix 12 of α- and β-tubulin is shown in light pink.

Figure 3

Sequence alignment of critical elements of the motor domain associated with MT depolymerization for the Kinesin-13 (Kif2C) and for the Kinesin-8 (Kif19A, Kip3, and Kif18A) proteins. Identical residues are shown in red, similar residues are shown in blue, and dissimilar residues are shown in black. β-sheet residues on either side of loop L2 are included. Clustal W was used for sequence alignment. Accession numbers: mmKif2C NP_608301.3; mmKif19A NP_001096085.1; scKip3 KZV11013.1; hsKif18A NP_112494.3.