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Membrane-spanning ?-helical barrels as tractable protein-design targets.

ABSTRACT: The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The ?-helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix-helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful de novo designs. For one class, the ?-helical barrels-that is, symmetric bundles of five or more helices with central accessible channels-there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble ?-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning ?-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and de novo protein design.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.

SUBMITTER: Niitsu A

PROVIDER: S-EPMC5483516 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Membrane-spanning α-helical barrels as tractable protein-design targets.

Niitsu Ai A Heal Jack W JW Fauland Kerstin K Thomson Andrew R AR Woolfson Derek N DN

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20170801 1726

The rational (<i>de novo</i>) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source ...[more]

PMID: 28630153

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Project description:BackgroundIn genomics and proteomics, membrane protein analysis have shown that such analyses are very important to support the understanding of complex biological processes. In Genome-wide investigations of membrane proteins a large number of short, distinct sequence motifs has been revealed. Such motifs found so far support the understanding of the folded membrane protein in the membrane environment. They provide important information about functional or stabilizing properties. Recently several integrative approaches have been proposed to extract meaningful information out of the membrane environment. However, many information based approaches deliver results having deficits of visualisation outputs. Outgoing from high-throughput protein data analysis, these outputs play an important role in the evaluation of high-dimensional protein data, to establish a biological relationship and ultimately to provide useful information for research.ResultsWe have evaluated different resulting graphs generated from statistical analysis of consecutive motifs in helical structures of the membrane environment. Our results show that representative motifs with high occurrence in all investigated protein families are responsible for the general importance in alpha-helical membrane structure formation. Further, motifs which often occur with others in their function as so called "hubs" lead to the assumption, that these motifs constitute as important components in helical structures within the membrane. Otherwise, consecutive motifs and hubs which show a high occurrence in certain families only can be classified as important for family-specific functional characteristics. Summarized, we are able to bridge our graphical results from high-throughput analysis of membrane proteins over networking with databases to a biological context.ConclusionsOur results and the corresponding graphical visualisation support the understanding and interpretation of structure forming and functional motifs of membrane proteins. Our results are useful to interpret and refine results of common developed approaches. At last we show a simple way to visualise high-dimensional protein data in context to biological relevant information.

Dataset Information

Membrane-spanning ?-helical barrels as tractable protein-design targets.

Publications

Membrane-spanning α-helical barrels as tractable protein-design targets.

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