Recognition of physiological phosphorylation sites by p21-activated kinase 4

Chetty, Ashwin; Sexton, Joel A.; Ha, Byung Hak; Turk, Benjamin E.; Boggon, Titus J.

doi:10.1016/j.jsb.2020.107553

Cited by 9 publications

(11 citation statements)

References 64 publications

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“…A recent study provided strong evidence for the role of position 189 as an L-5 determinant from a comparative structural analysis of L-5 and R-5 kinases ( Chen et al., 2017 ). This follows from a previous covariation-based approach used to demonstrate that position 144 (DFG+1) helps determine the S versus T phosphoacceptor preference ( Chen et al., 2014 ; Chetty et al., 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Sequence and Structure-Based Analysis of Specificity Determinants in Eukaryotic Protein Kinases

et al. 2021

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Section: Resultsmentioning

confidence: 99%

Sequence and Structure-Based Analysis of Specificity Determinants in Eukaryotic Protein Kinases

et al. 2021

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“…This may potentiate lipid peroxidation and consequent disruption of the mitochondrial membrane potential [25]. Oxidative stress can also the switch of the ATP synthase enzyme from to that of hydrolysis [26]. The serum level of liver enzymes (AST, ALT, ALP and GGT) were increased in animals administered fractions of P. zeylanica (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fractions of Aqueous Extract of Plumbago zeylanica (L.) Root Induced Mitochondrial Membrane Permeability Transition Pore Opening in Rats

Olanrewaju

Ehigie²,

Oyelere³

et al. 2022

IJBcRR

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Mitochondrial membrane permeability pore opening is recognized as a molecular mechanism involved in programmed cell death. The purpose of this study was to evaluate the effects of certain fractions crude aqueous extract of the root bark of Plumbago zeylanica (PZ) on the opening of the mitochondrial membrane permeability transition pore in rat liver. Pore opening, mitochondrial ATPase activity, lipid peroxidation and liver function markers were assessed spectrophotometrically while caspase 9 activity and liver morphology were monitored by immunohistochemistry and histology respectively. All fractions of PZ induced pore opening and enhanced the activity of caspase-9. Significant increases were observed in the mitochondrial ATPase activity while the level of malondialdehyde was significantly reduced. Sinusoidal dilation and hypertrophy were observed in liver sections of treated rats. These results suggest that aqueous fractions of PZ have bioactive agents capable of altering mitochondrial bioenergetics and inducing the opening of MMPT pore with mild hepatotoxicity.

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“…As a consequence, the LIMK kinase activity is increased dramatically [ 10 ]. An interesting aspect of LIMK activation is observed with the upstream kinase PAK4, which prefers phosphorylating its substrates at serine residues [ 18 ]. Accordingly, all validated PAK4 substrates except for LIMK1 are phosphorylated at serine residues, and consequently the LIMK1 variant T508S is a much better substrate for PAK4 than LIMK1 WT.…”

Section: The Conformational Space Of the Limk Kinase Domainmentioning

confidence: 99%

“…Accordingly, all validated PAK4 substrates except for LIMK1 are phosphorylated at serine residues, and consequently the LIMK1 variant T508S is a much better substrate for PAK4 than LIMK1 WT. This represents an example of the physiological phosphorylation of a disfavoured kinase substrate [ 18 ].…”

Section: The Conformational Space Of the Limk Kinase Domainmentioning

confidence: 99%

Structural Aspects of LIMK Regulation and Pharmacology

Chatterjee

Preuß

Dederer

et al. 2022

Cells

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Malfunction of the actin cytoskeleton is linked to numerous human diseases including neurological disorders and cancer. LIMK1 (LIM domain kinase 1) and its paralogue LIMK2 are two closely related kinases that control actin cytoskeleton dynamics. Consequently, they are potential therapeutic targets for the treatment of such diseases. In the present review, we describe the LIMK conformational space and its dependence on ligand binding. Furthermore, we explain the unique catalytic mechanism of the kinase, shedding light on substrate recognition and how LIMK activity is regulated. The structural features are evaluated for implications on the drug discovery process. Finally, potential future directions for targeting LIMKs pharmacologically, also beyond just inhibiting the kinase domain, are discussed.

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Recognition of physiological phosphorylation sites by p21-activated kinase 4

Cited by 9 publications

References 64 publications

Sequence and Structure-Based Analysis of Specificity Determinants in Eukaryotic Protein Kinases

Sequence and Structure-Based Analysis of Specificity Determinants in Eukaryotic Protein Kinases

Fractions of Aqueous Extract of Plumbago zeylanica (L.) Root Induced Mitochondrial Membrane Permeability Transition Pore Opening in Rats

Structural Aspects of LIMK Regulation and Pharmacology

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