Dataset Information

Study of Functional and Allosteric Sites in Protein Superfamilies.

ABSTRACT: The interaction of proteins (enzymes) with a variety of low-molecular-weight compounds, as well as protein-protein interactions, is the most important factor in the regulation of their functional properties. To date, research effort has routinely focused on studying ligand binding to the functional sites of proteins (active sites of enzymes), whereas the molecular mechanisms of allosteric regulation, as well as binding to other pockets and cavities in protein structures, remained poorly understood. Recent studies have shown that allostery may be an intrinsic property of virtually all proteins. Novel approaches are needed to systematically analyze the architecture and role of various binding sites and establish the relationship between structure, function, and regulation. Computational biology, bioinformatics, and molecular modeling can be used to search for new regulatory centers, characterize their structural peculiarities, as well as compare different pockets in homologous proteins, study the molecular mechanisms of allostery, and understand the communication between topologically independent binding sites in protein structures. The establishment of an evolutionary relationship between different binding centers within protein superfamilies and the discovery of new functional and allosteric (regulatory) sites using computational approaches can improve our understanding of the structure-function relationship in proteins and provide new opportunities for drug design and enzyme engineering.

SUBMITTER: Suplatov D

PROVIDER: S-EPMC4717248 | biostudies-literature | 2015 Oct-Dec

REPOSITORIES: biostudies-literature

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Study of Functional and Allosteric Sites in Protein Superfamilies.

Suplatov D D Švedas V V

Acta naturae 20151001 4

The interaction of proteins (enzymes) with a variety of low-molecular-weight compounds, as well as protein-protein interactions, is the most important factor in the regulation of their functional properties. To date, research effort has routinely focused on studying ligand binding to the functional sites of proteins (active sites of enzymes), whereas the molecular mechanisms of allosteric regulation, as well as binding to other pockets and cavities in protein structures, remained poorly understo ...[more]

PMID: 26798490

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Project description:BACKGROUND: With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional drug discovery approach of targeting active sites can be extended by targeting allosteric or regulatory protein pockets that may allow the discovery of not only novel drug-like inhibitors, but activators as well. The wealth of available protein structural data can be exploited to further increase our understanding of allosterism, which in turn may have therapeutic applications. A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data. RESULTS: We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across protein families. CONCLUSIONS: Our results show that structurally conserved pockets are a common feature of protein families. The structural conservation of protein pockets, combined with other characteristics, can be exploited in drug discovery procedures, in particular for the selection of the most appropriate target protein and pocket for the design of drugs against entire protein families or subfamilies (e.g. for the development of broad-spectrum antimicrobials) or against a specific protein (e.g. in attempting to reduce side effects).

Project description:We present, to our knowledge, the first quantitative analysis of functional site diversity in homologous domain superfamilies. Different types of functional sites are considered separately. Our results show that most diverse superfamilies are very plastic in terms of the spatial location of their functional sites. This is especially true for protein-protein interfaces. In contrast, we confirm that catalytic sites typically occupy only a very small number of topological locations. Small-ligand binding sites are more diverse than expected, although in a more limited manner than protein-protein interfaces. In spite of the observed diversity, our results also confirm the previously reported preferential location of functional sites. We identify a subset of homologous domain superfamilies where diversity is particularly extreme, and discuss possible reasons for such plasticity, i.e. structural diversity. Our results do not contradict previous reports of preferential co-location of sites among homologues, but rather point at the importance of not ignoring other sites, especially in large and diverse superfamilies. Data on sites exploited by different relatives, within each well annotated domain superfamily, has been made accessible from the CATH website in order to highlight versatile superfamilies or superfamilies with highly preferential sites. This information is valuable for system biology and knowledge of any constraints on protein interactions could help in understanding the dynamic control of networks in which these proteins participate. The novelty of our work lies in the comprehensive nature of the analysis - we have used a significantly larger dataset than previous studies - and the fact that in many superfamilies we show that different parts of the domain surface are exploited by different relatives for ligand/protein interactions, particularly in superfamilies which are diverse in sequence and structure, an observation not previously reported on such a large scale. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

Project description:Heat shock protein 20 (Hsp20) genes play important roles in plant growth, development, and response to environmental stress. However, the Hsp20 gene family has not yet been systematically investigated, and its function in red algae (Rhodophyta) remains poorly understood. Herein, we characterized Hsp20 gene families in red algae by studying gene structure, conserved motifs, phylogenetic relationships, chromosome location, gene duplication, cis-regulatory elements, and expression profiles. In this study, 97 Hsp20 genes were identified using bioinformatic methods and classified into 13 subfamilies based on phylogenetic relationships. Phylogenetic analysis revealed that Hsp20 genes might have a polyphyletic origin and a complex evolutionary pattern. Gene structure analysis revealed that most Hsp20 genes possessed no introns, and all Hsp20 genes contained a conserved α-crystalline domain in the C-terminal region. Conserved motif analysis revealed that Hsp20 genes belonging to the same subfamily shared similar motifs. Gene duplication analysis demonstrated that tandem and segmental duplication events occurred in these gene families. Additionally, these gene families in red algae might have experienced strong purifying selection pressure during evolution, and Hsp20 genes in Pyropia yezoensis, Pyropia haitanensis, and Porphyra umbilicalis were highly evolutionarily conserved. The cis-elements of phytohormone-, light-, stress-responsive, and development-related were identified in the red algal Hsp20 gene promoter sequences. Finally, using Py. yezoensis, as a representative of red algae, the Hsp20 gene expression profile was explored. Based on the RNA-seq data, Py. yezoensis Hsp20 (PyyHsp20) genes were found to be involved in Py. yezoensis responses against abiotic and biotic stresses and exhibited diverse expression patterns. Moreover, PyyHsp20 is involved in Py. yezoensis growth and development and revealed spatial and temporal expression patterns. These results provide comprehensive and valuable information on Hsp20 gene families in red algae and lay a foundation for their functional characterization. In addition, our study provides new insights into the evolution of Hsp20 gene families in red algae and will help understand the adaptability of red algae to diverse environments.

Dataset Information

Study of Functional and Allosteric Sites in Protein Superfamilies.

Publications

Study of Functional and Allosteric Sites in Protein Superfamilies.

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