6c9d | pdb_00006c9d

Crystal structure of KA1-autoinhibited MARK1 kinase

spinqualitylabelsall models 6c9d, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6c9d is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.499Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MARK1_HUMAN Note=Genetic variations in MARK1 may be associated with susceptibility to autism. MARK1 is overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites. Function MARK1_HUMAN Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2, MAP4 and MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Publication Abstract from PubMed The kinase associated-1 (KA1) domain is found at the C-terminus of multiple Ser/Thr protein kinases from yeast to humans, and has been assigned autoinhibitory, membrane-binding, and substrate-targeting roles. Here, we report the crystal structure of the MARK1 kinase/UBA domain bound to its autoinhibitory KA1 domain, revealing an unexpected interface at the alphaD helix and contacts with both the N- and C-lobes of the kinase domain. We confirm the binding interface location in kinetic studies of variants mutated on the kinase domain surface. Together with other MARK kinase structures, the data implicate that the KA1 domain blocks peptide substrate binding. The structure highlights the kinase-specific autoinhibitory binding modes of different KA1 domains, and provides potential new avenues by which to intervene therapeutically in Alzheimer's disease and cancers in which MARK1 or related kinases are implicated. Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain.,Emptage RP, Lemmon MA, Ferguson KM, Marmorstein R Structure. 2018 Aug 7;26(8):1137-1143.e3. doi: 10.1016/j.str.2018.05.008. Epub, 2018 Jun 28. PMID:30099988 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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