Crystal structure of domain‐swapped STE20 OSR1 kinase domain

Lee, Seung-Jae; Cobb, Melanie H.; Goldsmith, Elizabeth J.

doi:10.1002/pro.27

Cited by 60 publications

(77 citation statements)

References 55 publications

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“…Such highly coordinated interactions likely reduce the mobility of the loop compared with its unmodified state and can only be achieved by a phosphorylated residue, perhaps explaining why the TBK1 S172E phosphomimetic mutant shows decreased activity compared with the wild-type enzyme (20). The conformational change nucleated by the phosphorylation of S172 further propagates to the rest of the activation loop, resulting in intramolecular docking of the HPD motif onto the kinase C lobe and completion of the P+1 pocket, thus providing the full complement of interactions required to facilitate phosphotransfer to polypeptide substrates (23,35). Accordingly, pS172-activated TBK1 can quickly catalyze the modification of other TBK1 molecules, likely constituting the second rapid phase observed in TBK1 autoactivation reactions.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Ma¹,

Helgason

Phung³

et al. 2012

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

193

227

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Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptormediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events. Phosphorylation promotes the dimerization and nuclear translocation of these transcription factors that stimulate production of type I interferons (IFNs) (1,3,5). Recent studies have identified an additional role for TBK1 in the xenophagic elimination of bacteria (6-9) and better-defined how cross-talk within the IKK family regulates innate immune response (10).Under pathological conditions, IKK-mediated pathways can also be activated inappropriately by endogenous signals, contributing to inflammatory disorders and oncogenesis (11,12). Whereas canonical IKKs have long been recognized as bridges between chronic inflammation and cancer, IKK-related kinases more recently have also been implicated in cell transformation and tumor progression (13). TBK1 has been of particular interest, given its identification both as an activator of the oncogenic AKT kinase (14-18) and as an essential factor in KRAS-driven cancers (19).TBK1 activity is regulated by phosphorylation on S172 within the classical kinase activation loop. Serine-to-alanine substitution at this position abolishes TBK1 activity, whereas the phosphomimetic mutation S172E partially restores activity to within ∼200-fold of the wild-type kinase (20). Genetic and pharmacological inhibition studies have indicated that TBK1 can be activated by IKKβ, as well as by apparent autophosphorylation (10). Additional posttranslational modifications of TBK1 lysine residues by K63-linked polyubiquitin chains have been shown to promote production of IFNs in viral infections (21).TBK1 contains a predicted ubiquitin-like domain (ULD) (22) that is located between the N-terminal kinase domain (KD) and the C-terminal scaffolding/dimerization domain (SDD), a domain arrangement that appears to be shared among the IKK family of kinases (3). Deletion or mutation of the ULD in TBK1 or IKKε severely impairs kinase activation and substrate phosphorylation in cells (22,23). Furthermore, the integrity of the ULD in IKKβ is not only required for kinase activity (24) bu...

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Section: Discussionmentioning

confidence: 99%

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Ma¹,

Helgason

Phung³

et al. 2012

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

193

227

View full text Add to dashboard Cite

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“…The structure of the OSR1 kinase domain, as determined by crystallography, revealed that OSR1 is capable of forming dimers, likely as a part of the kinase activation process (34). Structural elements in OSR1 that are involved in dimerization are also found in SPAK, raising the possibility that SPAK and OSR1 form heterodimers.…”

Section: Discussionmentioning

confidence: 99%

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

Grimm

Taneja

Liu

et al. 2012

Journal of Biological Chemistry

123

159

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Background: Full-length SPAK is thought to be necessary and sufficient to activate NCC in the distal convoluted tubule (DCT). Results: SPAK knock-out disrupts a signaling network, involving OSR1, in the DCT but not the TAL, preventing NCC activation. Conclusion: SPAK and OSR1 function interdependently in the DCT to positively regulate NCC. Significance: This study provides insights into the mechanisms whereby SPAK/OSR1 regulates renal salt transport.

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“…Domain swapping for the isolated kinase domains of cell cycle checkpoint kinase 2, death-associated protein kinase 3, lymphocyte-oriented kinase, and Ste20-like kinase has been proposed as a possible mechanism of trans-auto phosphorylation at non-consensus sites (25,26). More recently, domain swapping has been observed for the isolated OSR1 kinase domain, which in contrast to cell cycle checkpoint kinase 2, death-associated protein kinase 3, lymphocyte-oriented kinase, and Ste20-like kinase, does not undergo autophosphorylation (27). Autophosphorylation has not been observed for p70S6KD.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Human p70 Ribosomal S6 Kinase-1 Regulation by Activation Loop Phosphorylation

Sunami¹,

Byrne

Diehl

et al. 2010

Journal of Biological Chemistry

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p70 ribosomal S6 kinase (p70S6K) is a downstream effector of the mTOR signaling pathway involved in cell proliferation, cell growth, cell-cycle progression, and glucose homeostasis. Multiple phosphorylation events within the catalytic, autoinhibitory, and hydrophobic motif domains contribute to the regulation of p70S6K. We report the crystal structures of the kinase domain of p70S6K1 bound to staurosporine in both the unphosphorylated state and in the 3-phosphoinositide-dependent kinase-1-phosphorylated state in which Thr-252 of the activation loop is phosphorylated. Unphosphorylated p70S6K1 exists in two crystal forms, one in which the p70S6K1 kinase domain exists as a monomer and the other as a domain-swapped dimer. The crystal structure of the partially activated kinase domain that is phosphorylated within the activation loop reveals conformational ordering of the activation loop that is consistent with a role in activation. The structures offer insights into the structural basis of the 3-phosphoinositide-dependent kinase-1-induced activation of p70S6K and provide a platform for the rational structure-guided design of specific p70S6K inhibitors.The ribosomal S6 kinase family belongs to the AGC 3 subfamily of serine-threonine protein kinases. In humans two forms of p70 ribosomal S6 kinases (S6K1 and S6K2) have been reported that are encoded by two different genes (RPS6KB1 and RPS6KB2), respectively (1, 2). RPS6KB1 encodes two isoforms that differ only at the N termini by 23 amino acid residues (2). The longer form of S6K1 contains an N-terminal nuclear localization signal, whereas the shorter isoform of S6K1 predominantly localizes in the cytosol.Several substrates of p70S6K have been identified including 40 S ribosomal protein S6, insulin substrate (IRS1), preapoptotic protein BAD, eukaryotic initiation factor (elF4B), eukaryotic elongation factor (eEF2K) and cAMP-response element modulator (CREMt) (3). The most studied substrate is the 40 S ribosomal protein S6, a major component of the machinery involved in protein synthesis in mammalian cells, suggesting that p70S6K plays a role in regulating translation.Several observations suggest a role for p70S6K in cancer (4, 5). For example, upstream regulators of p70S6K are deregulated in multiple types of cancer, and gene and protein overexpression is observed in various cancers (4, 5). In addition, p70S6K is also a downstream kinase of insulin receptor-mediated signaling and is a potential therapeutic target for the management of obesity and diabetes as shown by enhanced metabolic rate and insulin sensitivity in p70S6K knock-out mice (4, 5).The activation of p70S6K requires multiple phosphorylation events in both the kinase and autoinhibitory domains (Fig. 1). The C-terminal autoinhibitory domain, which is believed to block phosphorylation within the hydrophobic motif and the activation loop, is phosphorylated by upstream kinases such as ERK (6, 7). Other activating phosphorylation events occur at Thr-412 in the hydrophobic motif by mTOR (mammalian target of rapam...

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Crystal structure of domain‐swapped STE20 OSR1 kinase domain

Cited by 60 publications

References 55 publications

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

Structural Basis of Human p70 Ribosomal S6 Kinase-1 Regulation by Activation Loop Phosphorylation

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