Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases

Laughlin, John D.; Nwachukwu, Jerome C.; Figuera-Losada, Mariana; Cherry, Lisa; Nettles, K.W.; LoGrasso, Philip V.

doi:10.1016/j.str.2012.09.021

Cited by 36 publications

(49 citation statements)

References 48 publications

(68 reference statements)

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“…This approach allowed definition of the structural basis of differential ligand recognition by ERα versus ERβ 17 , partial agonist/graded signaling 4 and its control by ligand dynamics 5 and allostery in JNK family kinases 18 . While a comparison of two paired ligands could be informative, it is not possible to differentiate between class-specific phenotypes and attributes specific to the ligand.…”

Section: Resultsmentioning

confidence: 99%

Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α

et al. 2013

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Ligand-binding dynamics control allosteric signaling through the estrogen receptor-α (ERα), but the biological consequences of such dynamic binding orientations are unknown. Here, we compare a set of ER ligands having dynamic binding orientation (dynamic ligands) with a control set of isomers that are constrained to bind in a single orientation (constrained ligands). Proliferation of breast cancer cells directed by constrained ligands is associated with DNA binding, coactivator recruitment and activation of the estrogen-induced gene GREB1, reflecting a highly interconnected signaling network. In contrast, proliferation driven by dynamic ligands is associated with induction of ERα-mediated transcription in a DNA-binding domain (DBD)-dependent manner. Further, dynamic ligands displayed enhanced anti-inflammatory activity. The DBD-dependent profile was predictive of these signaling patterns in a larger diverse set of natural and synthetic ligands. Thus, ligand dynamics directs unique signaling pathways, and reveals a novel role of the DBD in allosteric control of ERα-mediated signaling.

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Section: Resultsmentioning

confidence: 99%

Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α

et al. 2013

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“…While most examples of these JIP1-or NFAT4-type docking motifs have been described in JNK1-interacting proteins, the docking surfaces of JNK1, JNK2, and JNK3 are near identical. That the interaction interfaces for the different JNKs will be very similar is supported by the structures of JNK3-JIP1 and JNK3-Sab complexes, which are nearly identical to the JNK1-JIP1 complex (202). The same D-motifs for JNK1 and JNK3 (at least for the short splice isoforms) also are likely to function equally well (158).…”

Section: Jnk Recognition Of Its Partner Regulators and Substrates Docmentioning

confidence: 88%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

387

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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“…The two different conformations resemble active-and auto-inhibited forms of JNK1, suggesting that the changes in structure resulting from the two different peptide-binding modes are related to kinase function (Fig. S8D) (37).…”

Section: Discussionmentioning

confidence: 98%

Structure and dynamics of the MKK7–JNK signaling complex

Kragelj

Palencia

Nanao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signaling specificity in the mitogen-activated protein kinase (MAPK) pathways is controlled by disordered domains of the MAPK kinases (MKKs) that specifically bind to their cognate MAPKs via linear docking motifs. MKK7 activates the c-Jun N-terminal kinase (JNK) pathway and is the only MKK containing three motifs within its regulatory domain. Here, we characterize the conformational behavior and interaction mechanism of the MKK7 regulatory domain. Using NMR spectroscopy, we develop an atomic resolution ensemble description of MKK7, revealing highly diverse intrinsic conformational propensities of the three docking sites, suggesting that prerecognition sampling of the bound-state conformation is not prerequisite for binding. Although the different sites exhibit similar affinities for JNK1, interaction kinetics differ considerably. Importantly, we determine the crystal structure of JNK1 in complex with the second docking site of MKK7, revealing two different binding modes of the docking motif correlating with observations from NMR exchange spectroscopy. Our results provide unique insight into how signaling specificity is regulated by linear motifs and, in general, into the role of conformational disorder in MAPK signaling.itogen-activated protein kinases (MAPKs) are essential components of eukaryotic signal transduction networks that enable cells to respond appropriately to extracellular stimuli (1). The MAPK signaling pathways feature three sequentially acting protein kinases making up a signaling module: an MKKK (MAPK kinase kinase) that phosphorylates and thereby activates an MKK (MAPK kinase), which then activates the MAPK by phosphorylation. In mammalian organisms, four major MAPK pathways have been identified: extracellular-signal-regulated kinase (ERK1/2), ERK5, p38α/β/γ/δ, and c-Jun N-terminal kinase (JNK1/2/3) (2).Seven human MKKs phosphorylate ERK, p38, and JNK according to the following selectivity scheme: MKK1/2 activate ERK1/2, MKK5 activates ERK5, MKK3/4/6 activate p38, and MKK4/7 activate JNK (3). Signaling specificity is controlled by intrinsically disordered N-terminal regulatory domains of the MKKs (ranging between 40 and 100 aa in length) that selectively bind to their cognate MAPKs (4-8). In the absence of these regulatory domains, phosphorylation of the downstream kinases is extremely inefficient (9, 10). Molecular recognition occurs through so-called docking sites in the regulatory domains composed of two to three basic residues followed by a short spacer of one to six residues and finally a hydrophobic-X-hydrophobic submotif. Crystal structures of ERK, p38, and JNK in complex with docking site peptides show that the basic residues contact the negatively charged common docking groove of the MAPKs, whereas the hydrophobic residues insert into hydrophobic pockets on the surface (Fig. S1A) (7,(11)(12)(13)(14)(15)(16).MKK7 activates the JNK pathway that primarily regulates stress and inflammatory responses. MKK7 is the only human MKK for which three putative docking sites (D1, D2, and D3) are pre...

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Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases

Cited by 36 publications

References 48 publications

Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α

Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Structure and dynamics of the MKK7–JNK signaling complex

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