Annotating proteins with generalized functional linkages

Llewellyn, Richard; Eisenberg, David

doi:10.1073/pnas.0809583105

Cited by 14 publications

(11 citation statements)

References 26 publications

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“…Such tentative functional assignments are often incorrect [2]. Furthermore, one annotation error can propagate or "percolate" [2-4] in databases as additional proteins are annotated by automated or semi-automated means.…”

Section: Introductionmentioning

confidence: 99%

Protein function annotation with Structurally Aligned Local Sites of Activity (SALSAs)

et al. 2013

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BackgroundThe prediction of biochemical function from the 3D structure of a protein has proved to be much more difficult than was originally foreseen. A reliable method to test the likelihood of putative annotations and to predict function from structure would add tremendous value to structural genomics data. We report on a new method, Structurally Aligned Local Sites of Activity (SALSA), for the prediction of biochemical function based on a local structural match at the predicted catalytic or binding site.ResultsImplementation of the SALSA method is described. For the structural genomics protein PY01515 (PDB ID 2aqw) from Plasmodium yoelii, it is shown that the putative annotation, Orotidine 5'-monophosphate decarboxylase (OMPDC), is most likely correct. SALSA analysis of YP_001304206.1 (PDB ID 3h3l), a putative sugar hydrolase from Parabacteroides distasonis, shows that its active site does not bear close resemblance to any previously characterized member of its superfamily, the Concanavalin A-like lectins/glucanases. It is noted that three residues in the active site of the thermophilic beta-1,4-xylanase from Nonomuraea flexuosa (PDB ID 1m4w), Y78, E87, and E176, overlap with POOL-predicted residues of similar type, Y168, D153, and E232, in YP_001304206.1. The substrate recognition regions of the two proteins are rather different, suggesting that YP_001304206.1 is a new functional type within the superfamily. A structural genomics protein from Mycobacterium avium (PDB ID 3q1t) has been reported to be an enoyl-CoA hydratase (ECH), but SALSA analysis shows a poor match between the predicted residues for the SG protein and those of known ECHs. A better local structural match is obtained with Anabaena beta-diketone hydrolase (ABDH), a known β-diketone hydrolase from Cyanobacterium anabaena (PDB ID 2j5s). This suggests that the reported ECH function of the SG protein is incorrect and that it is more likely a β-diketone hydrolase.ConclusionsA local site match provides a more compelling function prediction than that obtainable from a simple 3D structure match. The present method can confirm putative annotations, identify misannotation, and in some cases suggest a more probable annotation.

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Section: Introductionmentioning

confidence: 99%

Protein function annotation with Structurally Aligned Local Sites of Activity (SALSAs)

et al. 2013

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“…Sequence homology to a protein of known function may also be insufficient. 44 Determination of the tertiary structure can delineate allergen function by defining the overall shape of the molecule and/or revealing specific functional residues. 45 The major dust mite allergens, Der p 1 and Der f 1, are cysteine proteases.…”

Section: Allergen Structure As a Determinant Of Allergic Diseasementioning

confidence: 99%

100 Years later: Celebrating the contributions of x-ray crystallography to allergy and clinical immunology

Pomés

Chruszcz

Gustchina

et al. 2015

Journal of Allergy and Clinical Immunology

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Current knowledge of molecules involved in immunology and allergic disease results from significant contributions of X-ray crystallography, a discipline that just celebrated its 100th anniversary. The histories of allergens and X-ray crystallography are intimately intertwined. The first enzyme structure to be determined was lysozyme, also known as the chicken food allergen Gal d 4. Crystallography determines the exact three-dimensional positions of atoms in molecules. Structures of molecular complexes in the disciplines of immunology and allergy have revealed the atoms involved in molecular interactions and in mechanisms of disease. These complexes include peptides presented by MHC class II molecules, cytokines bound to their receptors, allergen-antibody complexes, and innate immune receptors with their ligands. The information derived from crystallographic studies provides insights into the function of molecules. Allergen function is one of the determinants of environmental exposure, which is essential for IgE sensitization. Proteolytic activity of allergens or their capacity to bind lipopolysaccharides may also contribute to allergenicity. The atomic positions define the molecular surface that is accessible to antibodies. This surface in turn determines antibody specificity and cross-reactivity that are important factors for the selection of allergen panels used for molecular diagnosis and for the interpretation of clinical symptoms. This review celebrates the contributions of X-ray crystallography to clinical immunology and allergy, focusing on new molecular perspectives that influence the diagnosis and treatment of allergic diseases.

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“…Since the PSI has been primarily concerned with high volume structure determination and prompt public availability of protein structures, most of these protein structures lack reliable accompanying information regarding their biochemical function; in some cases, no functional annotation is given. Thus, most of these proteins are assigned a putative or possible function based on the closest sequence or structure match; however, these assignments are often incorrect [8–10] , and these incorrect functional labels can propagate within databases [11,12] .…”

Section: Introductionmentioning

confidence: 99%

Biochemical functional predictions for protein structures of unknown or uncertain function

Mills

Beuning

Ondrechen

2015

Computational and Structural Biotechnology Journal

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With the exponential growth in the determination of protein sequences and structures via genome sequencing and structural genomics efforts, there is a growing need for reliable computational methods to determine the biochemical function of these proteins. This paper reviews the efforts to address the challenge of annotating the function at the molecular level of uncharacterized proteins. While sequence- and three-dimensional-structure-based methods for protein function prediction have been reviewed previously, the recent trends in local structure-based methods have received less attention. These local structure-based methods are the primary focus of this review. Computational methods have been developed to predict the residues important for catalysis and the local spatial arrangements of these residues can be used to identify protein function. In addition, the combination of different types of methods can help obtain more information and better predictions of function for proteins of unknown function. Global initiatives, including the Enzyme Function Initiative (EFI), COMputational BRidges to EXperiments (COMBREX), and the Critical Assessment of Function Annotation (CAFA), are evaluating and testing the different approaches to predicting the function of proteins of unknown function. These initiatives and global collaborations will increase the capability and reliability of methods to predict biochemical function computationally and will add substantial value to the current volume of structural genomics data by reducing the number of absent or inaccurate functional annotations.

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Annotating proteins with generalized functional linkages

Cited by 14 publications

References 26 publications

Protein function annotation with Structurally Aligned Local Sites of Activity (SALSAs)

Protein function annotation with Structurally Aligned Local Sites of Activity (SALSAs)

100 Years later: Celebrating the contributions of x-ray crystallography to allergy and clinical immunology

Biochemical functional predictions for protein structures of unknown or uncertain function

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