2wzj
Catalytic and UBA domain of kinase MARK2/(Par-1) K82R, T208E double mutant
Structural highlights
FunctionMARK2_RAT Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4, MAPT/TAU and RAB11FIP2. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule-dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells.[1] [2] [3] [4] [5] 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 PubMedKinases of the MARK/Par-1 family of S/T protein kinases are regulators of diverse cellular processes in Caenorhabditis elegans, Drosophila, yeast, and mammalian cells. They are involved in nematode embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. MARK phosphorylates microtubule-associated proteins such as tau and is a key regulator of microtubule-based intracellular transport. Hyperphosphorylation of tau causes defects in neuronal transport and may induce abnormal aggregation of tau in Alzheimer disease and other tauopathies. Recent high-resolution structure analysis of MARK fragments covering the kinase domain and accessory regulatory domains has revealed important details regarding the autoregulation of MARK, but their interpretation has remained controversial. Here we focus on the structural aspects of MARK activity and autoregulation. Comparison of the available MARK structures with related kinases of the AMPK family and with new structures of MARK isoforms (MARK2 and 3) reveals unexpected structural similarities between these kinases that may help to resolve the existing controversies. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases.,Marx A, Nugoor C, Panneerselvam S, Mandelkow E FASEB J. 2010 Jun;24(6):1637-48. Epub 2010 Jan 13. PMID:20071654[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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