Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)

Petrvalská, Olívia; Košek, Dalibor; Kukačka, Zdeněk; Tošner, Zdeněk; Man, Petr; Večeř, Jaroslav; Heřman, Petr; Obšilová, Veronika; Obšil, Tomáš

doi:10.1074/jbc.m116.724310

Cited by 49 publications

(42 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ASK1(88-941) was monomeric in solution in our SAXS experiments, in contrast with previous reports regarding the isolated kinase domain (28,44), which may provide some insight into a potential activation mechanism. Our model do not preclude ASK kinase dimer formation, but the scattering data do suggest that it occurs less readily with longer proteins than the kinase domain.…”

Section: Discussioncontrasting

confidence: 50%

“…However, the presence of the C-erminal region of ASK1, which likely predisposes the protein to form oligomers, could enable kinase dimerization to predominate in the context of the full-length protein. In addition, 14-3-3 proteins bind adjacent to the kinase domain and can themselves form dimers (28). Active kinase dimers also would be analogous to RAF MAP3Ks, which have been the topic of intense study in the ERK pathways (54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

“…The N-terminal region of ASK1 also has been implicated in binding CIB1 to detect Ca 2+ -based stress signaling, and in binding Fbxo21 to trigger innate antiviral signaling, among other proteinprotein interactions (24)(25)(26). The region C terminal to the kinase is less well studied, but contains a 14-3-3 protein-binding site housed within a predicted disordered sequence (27,28), followed by a region proposed to promote constitutive oligomerization of ASK1 (26). This C-terminal oligomerization region of ASK1 also has the capacity to directly bind to HIV Vif-1 and promote the innate antiviral response by APOBEC3G (8).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Weijman

Kumar

Jamieson

et al. 2017

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

View full text Add to dashboard Cite

Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region reveals an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homology domain. Biochemical assays show that both a conserved surface on the pleckstrin homology domain and an intact TPR region are required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its pleckstrin homology domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.itogen-activated protein (MAP) kinase cascades transmit signals from membrane-associated receptors to intracellular targets to effect changes in cellular behavior. They form a hierarchical system in which activated upstream kinases (MAP3Ks) phosphorylate intermediate MAP kinase kinases (MAP2Ks), which in turn phosphorylate terminal MAP kinases, primarily ERK, p38, and JNK and their isoforms (1). Extensive studies have focused on the activation of RAS-RAF-MEK upstream in the ERK pathway and provided fertile ground for the discovery of new therapeutics (2). In contrast to the ERK pathway, which primarily promotes cellular proliferation, JNK and p38 phosphorylate a range of substrates to promote inflammation and cell death (1, 3). In addition, cross-regulation among the p38, JNK, and ERK pathways is important for the efficacy of various cancer therapies that are in use or in development (4, 5). Molecular details on the more diverse upstream regulation of the p38 and JNK pathways are currently less clear, however.Apoptosis signal-regulating kinases (ASK1-3) are MAP3Ks that trigger cellular responses to redox stress and inflammatory cytokines (6, 7) and play vital roles in innate immunity and viral infection (8-11). When activated, ASK1-3 activate JNK and p38 via phosphorylation of MAP2Ks (MKK3/4/6/7) (12). The key initiator role of ASK1-3 in this pathway means that either too much or too little ASK activity can have pathological effects. For instance, inhibiting ASK1 is beneficial against gastric cancer (13,14), but inactivating mutations in ASK1...

show abstract

Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Weijman

Kumar

Jamieson

et al. 2017

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

View full text Add to dashboard Cite

show abstract

“…proC2) and 14-3-3f had been unsuccessful, we decided to use small angle X-ray scattering (SAXS) combined with NMR, with chemical cross-linking coupled to MS and with fluorescence spectroscopy to characterize the solution structure and conformational behavior of this complex. We and others have successfully used a similar approach to characterize conformationally flexible 14-3-3 protein complexes [29][30][31][32][33][34].…”

Section: Resultsmentioning

confidence: 99%

14‐3‐3 protein masks the nuclear localization sequence of caspase‐2

et al. 2018

Self Cite

View full text Add to dashboard Cite

Caspase‐2 is an apical protease responsible for the proteolysis of cellular substrates directly involved in mediating apoptotic signaling cascades. Caspase‐2 activation is inhibited by phosphorylation followed by binding to the scaffolding protein 14‐3‐3, which recognizes two phosphoserines located in the linker between the caspase recruitment domain and the p19 domains of the caspase‐2 zymogen. However, the structural details of this interaction and the exact role of 14‐3‐3 in the regulation of caspase‐2 activation remain unclear. Moreover, the caspase‐2 region with both 14‐3‐3‐binding motifs also contains the nuclear localization sequence (NLS), thus suggesting that 14‐3‐3 binding may regulate the subcellular localization of caspase‐2. Here, we report a structural analysis of the 14‐3‐3ζ:caspase‐2 complex using a combined approach based on small angle X‐ray scattering, NMR, chemical cross‐linking, and fluorescence spectroscopy. The structural model proposed in this study suggests that phosphorylated caspase‐2 and 14‐3‐3ζ form a compact and rigid complex in which the p19 and the p12 domains of caspase‐2 are positioned within the central channel of the 14‐3‐3 dimer and stabilized through interactions with the C‐terminal helices of both 14‐3‐3ζ protomers. In this conformation, the surface of the p12 domain, which is involved in caspase‐2 activation by dimerization, is sterically occluded by the 14‐3‐3 dimer, thereby likely preventing caspase‐2 activation. In addition, 14‐3‐3 protein binding to caspase‐2 masks its NLS. Therefore, our results suggest that 14‐3‐3 protein binding to caspase‐2 may play a key role in regulating caspase‐2 activation. Database The atomic coordinates and structure factors have been deposited in the Protein Data Bank, http://www.ww pdb.org (PDB ID codes http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6GKF and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6GKG).

show abstract

“…Sequences C-terminal to the ASK1 kinase domain are known to play roles in binding regulatory proteins (19,20), and facilitating interactions between ASK proteins to generate oligomeric ASK signalosomes (17). While a coiled-coil region is predicted near the Cterminus of each ASK protein, the precise structural architecture of the C-terminal portion of ASK proteins is unclear.…”

Section: Ask1-3 C-terminal Domains Have Divergent Oligomerisation Promentioning

confidence: 99%

Mechanism of preferential complex formation by Apoptosis Signal-regulating Kinases

Burgess

et al. 2019

Preprint

View full text Add to dashboard Cite

Apoptosis signal-regulating kinases (ASK1-3) are activators of the P38 and JNK MAP kinase pathways. ASK1-3 form oligomeric complexes known as ASK signalosomes that initiate signalling cascades in response to diverse stress stimuli. Here we demonstrate that oligomerization of ASK proteins is driven by previously uncharacterised sterile-alpha motif (SAM) domains that reside at the C-terminus of each ASK protein. SAM domains from ASK1-3 have distinct behaviours: ASK1 forms unstable oligomers, ASK2 is predominantly monomeric, and the ASK3 SAM domain forms a stable oligomer even at low concentration.In contrast to their isolated behaviour, the ASK1 and ASK2 SAM domains preferentially form a stable heterocomplex. The crystal structure of the ASK3 SAM domain, small-angle X-ray scattering, and mutagenesis suggests that ASK3 oligomers and ASK1-ASK2 complexes form discrete quasi-helical rings, via the mid-loop-end-helix interface. Preferential ASK1-ASK2 binding is consistent with mass spectrometry showing that full-length ASK1 forms heterooligomeric complexes incorporating high levels of ASK2. Accordingly, disruption of SAM domain-association impairs ASK activity in the context of electrophilic stress induced by 4-hydroxy-2-nonenal. These findings provide a structural template for how ASK proteins assemble foci to drive inflammatory signalling, and reinforce that strategies targeting ASK kinases should consider the concerted actions of multiple ASK family members.

show abstract

Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)

Cited by 49 publications

References 49 publications

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

14‐3‐3 protein masks the nuclear localization sequence of caspase‐2

Mechanism of preferential complex formation by Apoptosis Signal-regulating Kinases

Contact Info

Product

Resources

About