Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Kornev, Alexandr P.; Haste, Nina M.; Taylor, Susan S.; Eyck, Lynn F. Ten

doi:10.1073/pnas.0607656103

Cited by 663 publications

(790 citation statements)

References 30 publications

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“…37 Correct geometry of the HRD catalytic motif (at positions 141-143) is imperative for kinase activity. 38 Thus, we predicted that mutation of the HRD motif to HGD in the R142G RIPK3 mutant would lead to conformational pliability within the catalytic loop and concomitant defective catalytic activity.…”

Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

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Section: Resultsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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“…The insertion of ATP compacts the binding cleft, stabilizing the interlobe contacts (see Fig. 1 B, D, and E) between the Mg 2ϩ binding loop and activation loop (residues 184-204) (36). ATP binding causes a clockwise rotation of the C-terminal tail, allowing Phe-327 to contact ATP (2), which further enhances the compaction between the small and large lobes.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of the closed form suggests that the hydrogen bond between His-87 and P-Thr-197 is a key element for this stabilization/activation. The P-Thr-197 also mediates repulsion between Arg-165 and Lys-189 and stabilizes the ␤6-␤9 sheet, leading to a cascade of hydrogen bonds that stabilize the catalytically important DFG motif (36). (iii) Although Glu-170 and Tyr-330 do not make a direct contact, this residue pair allows us to monitor the C-terminal tail position relative to the catalytic loop, informing on the progress made in transitions.…”

Section: Resultsmentioning

confidence: 99%

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Ligand-induced global transitions in the catalytic domain of protein kinase A

Hyeon

Jennings²,

Adams³

et al. 2009

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

112

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“…The primary phosphorylated amino acid [pThr197] forms the center of a network of interactions typically coordinating the catalytic loop, the DFG-motif and the helix aC (Fig. 2) [21]. The flexibility required for this peculiar conformation accounts for the exceptional conservation of [Gly186].…”

Section: Regulation Of the Conformational Equilibrium And Activity Ofmentioning

confidence: 99%

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

Rabiller

Getlik

Klüter

et al. 2010

Archiv der Pharmazie

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The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.

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Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Cited by 663 publications

References 30 publications

RIPK1- and RIPK3-induced cell death mode is determined by target availability

RIPK1- and RIPK3-induced cell death mode is determined by target availability

Ligand-induced global transitions in the catalytic domain of protein kinase A

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

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