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The 14-3-3 Proteins As Important Allosteric Regulators of Protein Kinases

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The 14-3-3 Proteins As Important Allosteric Regulators of Protein Kinases International Journal of Molecular Sciences Review The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases Veronika Obsilova 1,* and Tomas Obsil 1,2,* 1 Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic 2 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, 12843 Prague, Czech Republic * Correspondence: [email protected] (V.O.); [email protected] (T.O.); Tel.: +420-325-87-3513 (V.O.); +420-22-195-1303 (T.O.) Received: 29 October 2020; Accepted: 20 November 2020; Published: 21 November 2020 Abstract: Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein–protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein–protein interactions and discussing in detail both their structural aspects and functional consequences. Keywords: 14-3-3; kinase; phosphorylation; RAF kinase; ASK1; CaMKK2; PI4KB; LRRK2; PKC 1. Introduction Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Tight and precise kinase regulation is a prerequisite for normal cell functioning. Conversely, kinase dysregulation often leads to disease. The function of many kinases is regulated through protein–protein interactions. These interactions are in turn mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. 14-3-3-mediated regulation has already been demonstrated for more than 30 kinases, and more than 170 kinases contain phosphosites known to conform to 14-3-3-binding sites [1]. However, many details concerning these interactions, especially the exact role of 14-3-3 binding and the mechanism of action of 14-3-3-mediated kinase regulation, remain elusive because only a few 14-3-3:kinase complexes have been structurally characterized so far, mostly using low-resolution approaches [2–4]. Nevertheless, several structures of rapidly accelerated fibrosarcoma B-type (B-RAF) kinase bound to 14-3-3 have been recently solved, thus providing the first glimpse, at atomic resolution, into a structural mechanism of 14-3-3-mediated kinase regulation [5–8]. Considering the above, the aim of this review article is to provide an overview of the current knowledge on 14-3-3-mediated kinase regulation. Although previous studies have shown that 14-3-3 proteins are involved in the regulation of many kinases, this review focuses only on complexes, whose available data enabled more detailed mechanistic insight into the 14-3-3-mediated regulation. Based on these data, we discuss structural aspects and functional consequences of these important protein–protein interactions. Int. J. Mol. Sci. 2020, 21, 8824; doi:10.3390/ijms21228824 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 16 Int. J. Mol. Sci. 2020, 21, 8824 2 of 16 2. 14-3-3 Proteins 2.The 14-3-3 14-3-3 Proteins protein family encompasses structurally similar acidic proteins found in all eukaryotes.The 14-3-3Although protein 14-3-3 family proteins encompasses were structurally originally similar characterized acidic proteins as abundant found in allbrain eukaryotes. proteins in 1967,Although with no 14-3-3 clear proteinsfunction, were they originally were later characterized identified asasabundant universal brain adaptor proteins and in chaperon 1967, with proteins, no knownclear for function, interacting they werewith laterhundreds identified of other as universal proteins adaptor and for and participating chaperon proteins, in the known regulation for of almostinteracting every major with hundreds cellular ofpath otherway proteins [9–12]. and Since for participatingtheir discovery, in the seven regulation human of almost 14-3-3 every isoforms havemajor been cellular identified pathway α/β, [γ9–, 12ε, ].ζ/ Sinceδ, η, theirτ, σ, discovery,where α and seven δ humanare the14-3-3 phosphorylated isoforms have forms been identifiedof the β and ζ isoformsα/β, γ [13]., ", ζ Other/δ, η, τ organisms,, σ, where α suchand asδ are budding the phosphorylated yeast, contain forms only oftwo the isoforms,β and ζ isoformsBmh1 and [13 Bmh2,]. whereasOther plants organisms, express such 15 asdifferent budding 14-3-3 yeast, isoforms contain only[14,15]. two In isoforms, addition, Bmh1 14-3-3 and proteins Bmh2, form whereas a stable plants express 15 different 14-3-3 isoforms [14,15]. In addition, 14-3-3 proteins form a stable homo- or homo- or heterodimers, with each protomer consisting of nine tightly packed antiparallel α-helices, heterodimers, with each protomer consisting of nine tightly packed antiparallel α-helices, which create whichan amphipathiccreate an amphipathic ligand-binding ligand-binding groove (Figure groove1A) [ 16 ,(Figure17]. The 14-3-31A) [16,17]. dimers The can be14-3-3 destabilized dimers bycan be 58 destabilizedthe lipid sphingosine by the lipid and sphingosine phosphorylation and phosphorylation of Ser58 at the dimer of interface Ser at [the18,19 dimer] and itinterface has been shown[18,19] and it hasthat been such shown destabilization that such induces destabilization downregulation induces of Raf-MAPK downregulation and PI3K-Akt of Raf-MAPK signaling [20 and]. PI3K-Akt signaling [20]. FigureFigure 1. 1.CrystalCrystal structure structure ofof the the 14-3-3 14-3-3 protein prot withein boundwith phosphopeptides.bound phosphopeptides. (A) The 14-3-3 (A) bindingThe 14-3-3 bindingmotif motif of apoptosis of apoptosis signal-regulating signal-regul kinaseating 1 (ASK1) kinase (sequence 1 (ASK1) RSIpS (sequence966LPVP) bound RSIpS to966 humanLPVP) 14-3-3 boundζ to human(PDB 14-3-3 ID: 6EJL).ζ (PDB The ID: 14-3-3 6EJL). protein The molecule 14-3-3 protein is a dimer molecu with ale two-fold is a dimer symmetry, with anda two-fold each protomer symmetry, and consistseach protomer of nine antiparallelconsists of αnine-helices antiparallel and contains α-helices an amphipathic and contains groove an amphipathic which is a binding groove site which σ is a forbinding the phosphorylated site for the phosphorylated motifs; (B) the ternary motifs; complex (B) the between ternary human complex 14-3-3 between(shown human in green), 14-3-3σ the 14-3-3 binding motif pSer259 of C-RAF (shown in orange), and Cotylenin A (shown in gray) (PDB ID: (shown in green), the 14-3-3 binding motif pSer259 of C-RAF (shown in orange), and Cotylenin A 4IHL [21]). The 14-3-3σ residues that make polar contacts with the phosphopeptide and Cotylenin are (shown in gray) (PDB ID: 4IHL [21]). The 14-3-3σ residues that make polar contacts with the shown as sticks. The Cotylenin A considerably enhances the binding of the C-RAF pSer259-motif to phosphopeptide14-3-3. The figure and was Cotylenin prepared are with shown PyMOL as (https: sticks.//pymol.org The Cotylenin/2/). A considerably enhances the binding of the C-RAF pSer259-motif to 14-3-3. The figure was prepared with PyMOL (https://pymol.org/2/). Int. J. Mol. Sci. 2020, 21, 8824 3 of 16 3. 14-3-3 Protein-Dependent Regulation of Selected Kinases PhosphorylationInt. J. Mol. Sci. 2020, 21, byx FOR protein PEER REVIEW kinases governs many key cellular and extracellular processes3 of 16 by participating3. 14-3-3 inProtein-Dependent various signaling Regulation pathways. of Selected Therefore, Kinases tight kinase regulation is a key prerequisite for normal cell functioning and its dysfunction often leads to disease. Many kinases are regulated Phosphorylation by protein kinases governs many key cellular and extracellular processes by in the 14-3-3 protein-dependent manner; however, the structural data available so far enable a participating in various signaling pathways. Therefore, tight kinase regulation is a key prerequisite detailedfor understandingnormal cell functioning of these and regulations its dysfunction for often only leads a few to kinases. disease. Many In this kinases review are article, regulated we in discuss regulationthe 14-3-3 of RAF, protein-dependen ASK1, leucine-richt manner; however, repeat protein the structural kinase-2 data (LRRK2),available soprotein far enable kinase a detailed C (PKC), calciumunderstanding/calmodulin-dependent of these regulations protein kinasefor only kinase a few (CaMKK), kinases. andIn this phosphatidylinositol-4-kinase-III review article, we discuss β (PI4KB),regulation for which of RAF, the mechanistic ASK1, leucine-rich insights repeat into theirprotein 14-3-3 kinase-2 protein-mediated (LRRK2), protein regulation kinase C are(PKC), available. calcium/calmodulin-dependent protein kinase kinase (CaMKK), and 3.1. RAFphosphatidylinositol-4-kinase-III Kinases β (PI4KB), for which the mechanistic insights into their 14-3-3 protein-mediated regulation are available. RAF kinases are key components of the RAS-RAF-MEK-ERK signaling pathway. These kinases were among3.1. RAF theKinases first oncoproteins characterized in the 1980s, and B-RAF is the most frequently mutated proteinRAF kinases kinase are in key various components cancers, of withthe RAS-RAF-MEK-ERK V600E standing out signaling as the mostpathway. common These kinases and resistant mutationwere [ 22among,23]. Selectivethe first oncoproteins inhibitors targeting characterized RAF in proteins the 1980s, are and currently B-RAF atis variousthe most stagesfrequently of clinical trials becausemutated protein RAF activity kinase isin strictlyvarious regulated,cancers, with and V600E any misbalancestanding out inas ERKthe most signaling common activation and or dysregulationresistant mutation usually leads[22,23].
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