ArticlePloS one2010
Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 9 citations in OpenAlex.
- Integrated Computational Approaches and Tools forAllosteric Drug Discovery.International journal of molecular sciences · 2020Review
- Disease-relevant mutations alter amino acid co-evolution networks in the second nucleotide binding domain of CFTR.PloS one · 2020Article
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2 authors at 1 institution in 1 country.
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Abstract
Regulation of Pak2 activity involves at least two mechanisms: (i) phosphorylation of the conserved Thr(402) in the activation loop and (ii) interaction of the autoinhibitory domain (AID) with the catalytic domain. We collected 482 human protein kinase sequences from the kinome database and globally mapped the evolutionary interactions of the residues in the catalytic domain with Thr(402) by sequence-based statistical coupling analysis (SCA). Perturbation of Thr(402) (34.6%) suggests a communication pathway between Thr(402) in the activation loop, and Phe(387) (DeltaDeltaE(387F,402T) = 2.80) in the magnesium positioning loop, Trp(427) (DeltaDeltaE(427W,402T) = 3.12) in the F-helix, and Val(404) (DeltaDeltaE(404V,402T) = 4.43) and Gly(405) (DeltaDeltaE(405G,402T) = 2.95) in the peptide positioning loop. When compared to the cAMP-dependent protein kinase (PKA) and Src, the perturbation pattern of threonine phosphorylation in the activation loop of Pak2 is similar to that of PKA, and different from the tyrosine phosphorylation pattern of Src. Reciprocal coupling analysis by SCA showed the residues perturbed by Thr(402) and the reciprocal coupling pairs formed a network centered at Trp(427) in the F-helix. Nine pairs of reciprocal coupling residues crucial for enzymatic activity and structural stabilization were identified. Pak2, PKA and Src share four pairs. Reciprocal coupling residues exposed to the solvent line up as an activation groove. This is the inhibitor (PKI) binding region in PKA and the activation groove for Pak2. This indicates these evolutionary conserved residues are crucial for the catalytic activity of PKA and Pak2.
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