Paul, A and Subhadarshini, S and Srinivasan, N (2022) Pseudokinases repurpose flexibility signatures associated with the protein kinase fold for noncatalytic roles. In: Proteins: Structure, Function and Bioinformatics, 90 (3). pp. 747-764.
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Abstract
The bilobal protein kinase-like fold in pseudokinases lack one or more catalytic residues, conserved in canonical protein kinases, and are considered enzymatically deficient. Tertiary structures of pseudokinases reveal that their loops topologically equivalent to activation segments of kinases adopt contracted configurations, which is typically extended in active conformation of kinases. Herein, anisotropic network model based normal mode analysis (NMA) was conducted on 51 active conformation structures of protein kinases and 26 crystal structures of pseudokinases. Our observations indicate that although backbone fluctuation profiles are similar for individual kinase-pseudokinase families, low intensity mean square fluctuations in pseudo-activation segment and other sub-structures impart rigidity to pseudokinases. Analyses of collective motions from functional modes reveal that pseudokinases, compared to active kinases, undergo distinct conformational transitions using the same structural fold. All-atom NMA of protein kinase-pseudokinase pairs from each family, sharing high amino acid sequence identities, yielded distinct community clusters, partitioned by residues exhibiting highly correlated fluctuations. It appears that atomic fluctuations from equivalent activation segments guide community membership and network topologies for respective kinase and pseudokinase. Our findings indicate that such adaptations in backbone and side-chain fluctuations render pseudokinases competent for catalysis-independent roles. © 2021 Wiley Periodicals LLC.
Item Type: | Journal Article |
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Publication: | Proteins: Structure, Function and Bioinformatics |
Publisher: | John Wiley and Sons Inc |
Additional Information: | The copyright for this article belongs to the John Wiley and Sons Inc. |
Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
Date Deposited: | 03 Dec 2021 08:51 |
Last Modified: | 16 Jun 2022 07:01 |
URI: | https://eprints.iisc.ac.in/id/eprint/70643 |
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