Key Points
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'Inheritance through homology' is the most common and generally more accessible approach to function prediction, but orthology should be established where possible to improve confidence in predictions.
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The body of functional annotations of proteins is becoming increasingly computer-readable and is being organized in ways that can enhance the scope of in silico prediction methods.
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Significant advances in complete genome sequencing have resulted in a new generation of methods that exploit sequence analysis on the genome level.
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Curated protein family resources can often guide the assignment of protein functions and the detection of motifs or sequence patterns.
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New approaches are being developed to identify functional residues in proteins; these can then be applied to divide larger protein families into more specific functional subfamilies.
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There have been exciting new developments in databases of experimentally determined protein–protein interactions, as well as genomic inference methods for predicting these interactions.
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Non-homology-based function prediction methods that exploit the properties of sequences and not their evolutionary history are also becoming more successful.
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Recent Structural Genomics Initiatives (SGIs) are attempting to target functionally diverse relatives within protein families.
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Function prediction from structure can be achieved by global comparison of protein structures to detect homology or through the use of structural templates derived from the active sites of enzymes. It is also possible to explore the protein surface for sequence-conserved patches, clefts and electrostatic potentials.
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In general terms, it is best to seek and compare the results of several methods to predict the function of novel proteins. Meta-servers simplify this by providing easy access to a range of the best-performing methods.
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Future developments will see more efficient integration of prediction methods and experimental data; for example, microarrays, yeast two-hybrid screens and tandem affinity purification. Better understanding of the diversification of function in protein families will permit more sophisticated means of predicting function and functional networks.
Abstract
While the number of sequenced genomes continues to grow, experimentally verified functional annotation of whole genomes remains patchy. Structural genomics projects are yielding many protein structures that have unknown function. Nevertheless, subsequent experimental investigation is costly and time-consuming, which makes computational methods for predicting protein function very attractive. There is an increasing number of noteworthy methods for predicting protein function from sequence and structural data alone, many of which are readily available to cell biologists who are aware of the strengths and pitfalls of each available technique.
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Acknowledgements
We would particularly like to acknowledge E. Sideris for help with the figures in this manuscript.
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Supplementary information S1 (table): Online resources
This site is not intended to list all available online resources but rather those that are widely used, of high quality, and publicly available as of June 2007. (PDF 382 kb)
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Glossary
- Orthologue
-
A homologue that is found in separate species and has been separated by speciation rather than by a gene duplication event.
- Homologue
-
Protein sequences are homologous if they have descended, usually with divergence, from a common ancestral sequence.
- Paralogue
-
A homologue that is the product of a gene duplication event within a species.
- Phylogenetic tree
-
Shows the evolutionary inter-relationships among various species or other entities that are believed to have a common ancestor. Each node that has descendants represents the most recent common ancestor of those descendants, with edge lengths sometimes corresponding to time estimates.
- TIM barrel
-
Consists of eight α-helices and eight parallel β-strands that alternate along the peptide backbone. The structure is named after triose phosphate isomerase, a conserved glycolytic enzyme.
- Superposition
-
After equivalent residues in two protein structures have been determined, the coordinates of one protein can be transformed onto the other.
- Rossmann fold
-
Composed of three or more parallel β-strands linked by two α-helices and is found in proteins that bind nucleotides, such as the NAD and FMN co-factors.
- Superfamily
-
A group of evolutionarily related proteins that often have the same overall domain structure, but may have diverged beyond recognition at the sequence level.
- Structural template
-
Many methods of predicting function from structure involve listing specific residues and expected inter-atom distances in a template file, which can then be compared against other structures.
- SITE record
-
Part of a Protein Data Bank file containing details of which residues are relevant to the protein function (for example, those involved in substrate binding).
- De novo sequence method
-
A method that does not rely upon homology between sequences for transferring functional annotations but rather on the recognition of features such as residue composition and subcellular localization signals.
- Meta-server
-
In the context of this review, a meta-server is a gateway to a well-benchmarked set of prediction methods.
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Lee, D., Redfern, O. & Orengo, C. Predicting protein function from sequence and structure. Nat Rev Mol Cell Biol 8, 995–1005 (2007). https://doi.org/10.1038/nrm2281
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DOI: https://doi.org/10.1038/nrm2281
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