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Structural Basis for the Non-catalytic Functions of Protein Kinases.

ABSTRACT: Protein kinases are known primarily for their ability to phosphorylate protein substrates, which constitutes an essential biological process. Recently, compelling evidence has accumulated that the functions of many protein kinases extend beyond phosphorylation and include an impressive spectrum of non-catalytic roles, such as scaffolding, allosteric regulation, or even protein-DNA interactions. How the conserved kinase fold shared by all metazoan protein kinases can accomplish these diverse tasks in a specific and regulated manner is poorly understood. In this review, we analyze the molecular mechanisms supporting phosphorylation-independent signaling by kinases and attempt to identify common and unique structural characteristics that enable kinases to perform non-catalytic functions. We also discuss how post-translational modifications, protein-protein interactions, and small molecules modulate these non-canonical kinase functions. Finally, we highlight current efforts in the targeted design of small-molecule modulators of non-catalytic kinase functions, a new pharmacological challenge for which structural considerations are more important than ever.

SUBMITTER: Kung JE

PROVIDER: S-EPMC4706642 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Structural Basis for the Non-catalytic Functions of Protein Kinases.

Kung Jennifer E JE Jura Natalia N

Structure (London, England : 1993) 20160101 1

Protein kinases are known primarily for their ability to phosphorylate protein substrates, which constitutes an essential biological process. Recently, compelling evidence has accumulated that the functions of many protein kinases extend beyond phosphorylation and include an impressive spectrum of non-catalytic roles, such as scaffolding, allosteric regulation, or even protein-DNA interactions. How the conserved kinase fold shared by all metazoan protein kinases can accomplish these diverse task ...[more]

PMID: 26745528

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Project description:BackgroundProtein phosphorylation is a generic way to regulate signal transduction pathways in all kingdoms of life. In many organisms, it is achieved by the large family of Ser/Thr/Tyr protein kinases which are traditionally classified into groups and subfamilies on the basis of the amino acid sequence of their catalytic domains. Many protein kinases are multi-domain in nature but the diversity of the accessory domains and their organization are usually not taken into account while classifying kinases into groups or subfamilies.MethodologyHere, we present an approach which considers amino acid sequences of complete gene products, in order to suggest refinements in sets of pre-classified sequences. The strategy is based on alignment-free similarity scores and iterative Area Under the Curve (AUC) computation. Similarity scores are computed by detecting common patterns between two sequences and scoring them using a substitution matrix, with a consistent normalization scheme. This allows us to handle full-length sequences, and implicitly takes into account domain diversity and domain shuffling. We quantitatively validate our approach on a subset of 212 human protein kinases. We then employ it on the complete repertoire of human protein kinases and suggest few qualitative refinements in the subfamily assignment stored in the KinG database, which is based on catalytic domains only. Based on our new measure, we delineate 37 cases of potential hybrid kinases: sequences for which classical classification based entirely on catalytic domains is inconsistent with the full-length similarity scores computed here, which implicitly consider multi-domain nature and regions outside the catalytic kinase domain. We also provide some examples of hybrid kinases of the protozoan parasite Entamoeba histolytica.ConclusionsThe implicit consideration of multi-domain architectures is a valuable inclusion to complement other classification schemes. The proposed algorithm may also be employed to classify other families of enzymes with multi-domain architecture.

Dataset Information

Structural Basis for the Non-catalytic Functions of Protein Kinases.

Publications

Structural Basis for the Non-catalytic Functions of Protein Kinases.

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