Abstract
BackgroundThe serine/threonine mammalian Ste-20 like kinases (MSTs) are key regulators of apoptosis, cellular proliferation as well as polarization. Deregulation of MSTs has been associated with disease progression in prostate and colorectal cancer. The four human MSTs are regulated differently by C-terminal regions flanking the catalytic domains.Principal FindingsWe have determined the crystal structure of kinase domain of MST4 in complex with an ATP-mimetic inhibitor. This is the first structure of an inactive conformation of a member of the MST kinase family. Comparison with active structures of MST3 and MST1 revealed a dimeric association of MST4 suggesting an activation loop exchanged mechanism of MST4 auto-activation. Together with a homology model of MST2 we provide a comparative analysis of the kinase domains for all four members of the human MST family.SignificanceThe comparative analysis identified new structural features in the MST ATP binding pocket and has also defined the mechanism for autophosphorylation. Both structural features may be further explored for inhibitors design.Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Highlights
The Sterile-20 protein kinase (Ste20) was first identified in yeast as a key molecule involved in pheromone signaling [1] and has since been found to be involved in the regulation of a large number of diverse cellular functions including cell polarization [2,3], actin organization [4,5], regulation of exit from mitosis [6] and apoptosis [7,8].Subsequently several mammalian Ste20-like (MST) kinases sharing homology with the yeast ste20 were identified and grouped into two structurally distinct families: p21-activated kinase (PAK) and the germinal centre kinase (GCK) [9]
MST2 is involved in the LATS tumor suppressor pathway via complexation with human orthologue of Salvador (hSav), RASSF1A, Nore1 and LATS1, resulting in the phosphorylation of LATS1 and transcription of proapoptotic genes [26,27,28]
Overall structures: kinase domain The overall structure of the kinase domains of MST1, MST3 and
Summary
The Sterile-20 protein kinase (Ste20) was first identified in yeast as a key molecule involved in pheromone signaling [1] and has since been found to be involved in the regulation of a large number of diverse cellular functions including cell polarization [2,3], actin organization [4,5], regulation of exit from mitosis [6] and apoptosis [7,8].Subsequently several mammalian Ste20-like (MST) kinases sharing homology with the yeast ste20 were identified and grouped into two structurally distinct families: p21-activated kinase (PAK) and the germinal centre kinase (GCK) [9]. We present the crystal structure of the unphosphorylated kinase domain of human MST4 refined at 2.35 Aresolution in complex with an ATP mimetic quinazoline inhibitor. Structural differences resulted from differential phosphorylation states, complex with ligands and crystal forms provide information on the structural plasticity and regulation of this group of kinases (Figure 2).
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