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NMR solution structure of human Vaccinia-Related Kinase 1NMR solution structure of human Vaccinia-Related Kinase 1
Structural highlights
DiseaseVRK1_HUMAN Pontocerebellar hypoplasia type 1. The disease is caused by mutations affecting the gene represented in this entry. FunctionVRK1_HUMAN Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosphorylates ATF2 which activates its transcriptional activity.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedVaccinia-related kinase 1 (VRK1) is one of the mitotic kinases which 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, 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 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. NMR solution structure of human vaccinia-related kinase 1 (VRK1) reveals the C-terminal tail essential for its structural stability and autocatalytic activity.,Shin J, Chakraborty G, Bharatham N, Kang C, Tochio N, Koshiba S, Kigawa T, Kim W, Kim KT, Yoon HS J Biol Chem. 2011 May 12. PMID:21543316[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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