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2v62
From Proteopedia
STRUCTURE OF VACCINIA-RELATED KINASE 2
Structural highlights
Function[VRK2_HUMAN] Serine/threonine kinase that regulates several signal transduction pathways. Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes. Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription. Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1. Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins. Downregulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1. Blocks the phosphorylation of ERK in response to ERBB2 and HRAS. Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant.[1] [2] [3] [4] [5] [6] [7] Isoform 2 phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.[8] [9] [10] [11] [12] [13] [14] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAbout 10% of all protein kinases are predicted to be enzymatically inactive pseudokinases, but the structural details of kinase inactivation have remained unclear. We present the first structure of a pseudokinase, VRK3, and that of its closest active relative, VRK2. Profound changes to the active site region underlie the loss of catalytic activity, and VRK3 cannot bind ATP because of residue substitutions in the binding pocket. However, VRK3 still shares striking structural similarity with VRK2, and appears to be locked in a pseudoactive conformation. VRK3 also conserves residue interactions that are surprising in the absence of enzymatic function; these appear to play important architectural roles required for the residual functions of VRK3. Remarkably, VRK3 has an "inverted" pattern of sequence conservation: although the active site is poorly conserved, portions of the molecular surface show very high conservation, suggesting that they form key interactions that explain the evolutionary retention of VRK3. Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site.,Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G Structure. 2009 Jan 14;17(1):128-38. PMID:19141289[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Non-specific serine/threonine protein kinase | Arrowsmith, C H | Bunkoczi, G | Cooper, C | Delft, F Von | Edwards, A | Eswaran, J | Fedorov, O | Keates, T | Knapp, S | Rellos, P | Salah, E | Savitsky, P | Sundstrom, M | Ugochukwu, E | Weigelt, J | Atp-binding | Membrane | Nucleotide-binding | Transferase | Transmembrane
