NMR Solution Structure of Human Vaccinia-related Kinase 1 (VRK1) Reveals the C-terminal Tail Essential for Its Structural Stability and Autocatalytic Activity.
Summary of "NMR Solution Structure of Human Vaccinia-related Kinase 1 (VRK1) Reveals the C-terminal Tail Essential for Its Structural Stability and Autocatalytic Activity."
Vaccinia-related kinase 1 (VRK1) is one of the mitotic kinases that play important roles in cell cycle, nuclear condensation, and transcription regulation. Kinase domain structures of two other VRK family members (VRK2 and VRK3) have been determined previously. However, the structure of VRK1, the most extensively studied and constitutively active VRK member, is yet to be characterized. Here, we present the nuclear magnetic resonance (NMR) solution structure of a catalytically active form of human VRK1 with its extended C-terminal tail (residues 1-361). The NMR structure of human VRK1 reveals that the C-terminal tail orients toward the catalytic site and forms a number of interactions that are critical for structural stability and catalysis. The role of this unique C-terminal tail was further investigated by deletion mutant studies where deletion of the terminal tail resulted in a dramatic reduction in the autocatalytic activity of VRK1. NMR titration studies carried out with ATP or an ATP analog confirm that ATP/ATP analogs interact with all of the crucial residues present in important motifs of the protein kinase such as the hinge region, catalytic loop, DYG motif, and thereby suggest that the catalytic domain of VRK1 is not atypical. In addition to the conventional interactions, some of the residues present on the extended C-terminal tail also interact with the ligands. These observations also substantiate the role of the extended C-terminal tail in the biological activity of VRK1.
Affiliation
From the School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Journal Details
This article was published in the following journal.
Name: The Journal of biological chemistry
ISSN: 1083-351X
Pages: 22131-8
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21543316
- DOI: http://dx.doi.org/10.1074/jbc.M110.200162
Medical and Biotech [MESH] Definitions
Vaccinia Virus
The type species of ORTHOPOXVIRUS, related to COWPOX VIRUS, but whose true origin is unknown. It has been used as a live vaccine against SMALLPOX. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of VACCINIA VIRUS.
Map Kinase Kinase Kinase 5
A 150-kDa MAP kinase kinase kinase that may play a role in the induction of APOPTOSIS. It has specificity for MAP KINASE KINASE 3; MAP KINASE KINASE 4; and MAP KINASE KINASE 6.
Cdc2-cdc28 Kinases
A family of cell cycle-dependent kinases that are related in structure to CDC28 PROTEIN KINASE; S CEREVISIAE; and the CDC2 PROTEIN KINASE found in mammalian species.
Map Kinase Kinase Kinase 2
A 70-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 5. It is activated during the cellular response to GROWTH FACTORS, oxidative stress, and hyperosmotic conditions.
Map Kinase Kinase Kinase 1
A 195-kDa MAP kinase kinase kinase with broad specificity for MAP KINASE KINASES. It is found localized in the CYTOSKELETON and can activate a variety of MAP kinase-dependent pathways.
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