The MPS1 family of protein kinases

Abstract

MPS1 protein kinases are found widely, but not ubiquitously, in eukaryotes. This family of potentially dual-specific protein kinases is among several that regulate a number of steps of mitosis. The most widely conserved MPS1 kinase functions involve activities at the kinetochore in both the chromosome attachment and the spindle checkpoint. MPS1 kinases also function at centrosomes. Beyond mitosis, MPS1 kinases have been implicated in development, cytokinesis, and several different signaling pathways. Family members are identified by virtue of a conserved C-terminal kinase domain, though the N-terminal domain is quite divergent. The kinase domain of the human enzyme has been crystallized, revealing an unusual ATP-binding pocket. The activity, level, and subcellular localization of Mps1 family members are tightly regulated during cell-cycle progression. The mitotic functions of Mps1 kinases and their overexpression in some tumors have prompted the identification of Mps1 inhibitors and their active development as anticancer drugs.

Figure 1

Localization of Mps1 in vertebrate mitotic and interphase cells. (a) Kinetochore localization of yellow fluorescent protein (YFP) Mps1 in mitotic SW480 cells. Anti-centromere antibodies (ACA) and 4′,6-diamidino-2-phenylindole (DAPI) were used to stain kinetochores and chromosomes. (b) YFP Mps1 is localized to centrosomes and the cytosol during interphase. Centrosomes and nuclei were stained by anti-γ-tubulin and DAPI, respectively.

Figure 2

(a) Ribbon representation of the structure of the Mps1 catalytic domain. Key structural elements are labeled. The structure has been rendered from the Protein Data Bank (PDB) entry 3DBQ, using the Maestro interface from Schrödinger. The dotted lines represent the disordered regions in the activation loop, the loop between αEF and αF and also at the C-terminal tail. (b) Ribbon representation of the structure of Mps1 in complex with a small-molecule inhibitor, Mps1-IN-1. The structure has been rendered from the PDB entry 3GFW using the Maestro interface. The residues in the hinge region are shown. (c) Illustration of the inhibitor-binding mode. The gatekeeper residue M602, hinge region residues that interact with the inhibitor and the ATP-binding pocket are shown. The dotted lines represent hydrogen bonds.

Figure 3

Multiple sequence alignment of the kinase domain of Mps1 from representative species using PRALINE multiple sequence alignment (http://www.ibi.vu.nl/programs/pralinewww/). Amino acid conservation is shown by a color-coded heat map from unconserved to conserved. The secondary structure of Mps1 is shown above the Mps1. Key amino acid residues are shown below the alignment.