6c9d
Crystal structure of KA1-autoinhibited MARK1 kinase
Structural highlights
DiseaseMARK1_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. FunctionMARK1_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).[1] [2] Publication Abstract from PubMedThe 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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