Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jun;19(3):363-8.
doi: 10.1016/j.sbi.2009.02.001. Epub 2009 Mar 5.

Is protein classification necessary? Toward alternative approaches to function annotation

Donald Petrey  1 , Barry Honig
Affiliations
Review

Is protein classification necessary? Toward alternative approaches to function annotation

Donald Petrey et al. Curr Opin Struct Biol. 2009 Jun.

Abstract

The current nonredundant protein sequence database contains over seven million entries and the number of individual functional domains is significantly larger than this value. The vast quantity of data associated with these proteins poses enormous challenges to any attempt at function annotation. Classification of proteins into sequence and structural groups has been widely used as an approach to simplifying the problem. In this article we question such strategies. We describe how the multifunctionality and structural diversity of even closely related proteins confounds efforts to assign function on the basis of overall sequence or structural similarity. Rather, we suggest that strategies that avoid classification may offer a more robust approach to protein function annotation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Relationships between three all-β proteins that have been classified as belonging to different folds/topologies. A) Secondary structure elements. Boxes represent β-strands that are perpendicular to the plane of the page. Strands marked with an ‘X’ are directed into the page and those marked with a ‘●’ are directed out of the page. The substructure conserved between all three proteins is shown in black and the nonconserved strands are shown in red. Except for a β-hairpin in the jelly-roll like proteins, all non-conserved strands occur at the N and C-termini of the conserved region and are easily accommodated structurally. B) Similarities between the biological roles of the three proteins. The jelly-roll and β-propeller are known experimentally to be involved in membrane binding associated with viral and bacterial entry into the cell, respectively. As summarized in the text, we suggest that the function of β-prism like proteins might involve the fusion of the phagosome with the lysozome.
Figure 2
Figure 2
Schematic of an interactive approach to function annotation. On the left of the figure a query protein and structurally similar proteins are represented in a manner similar to BLAST output. Interactive tools can then be used to address two types of biological questions. In the upper right, a functionally important region (enclosed by the black rectangle) is identified, based on properties such as sequence conservation, electrostatic conservation, and/or the presence of a surface cavity. UniProt features that represent known functions that occur in structural neighbors in similar locations are “mapped” to the alignment. (magenta rectangles). In the lower right, the initial set of proteins that are structurally similar to the query is filtered based on a known function of interest. The resulting reduced set can then be further analyzed to identify the structural determinants of that function.
Figure 3
Figure 3
Functional motifs in thioredoxins. The multiple sequence alignment shows the primary functional regions, a strand-loop-helix containing the catalytic cysteines, of three members of the thioredoxin superfamily (strand=yellow bar, helix=red bar). As illustrated, the GO term “protein disulfide oxidoreductase” is associated with the two cysteines (shown in blue) that determine this functionality specific to thioredoxins while the term “iron-sulfur cluster assembly” is associated with that functionality in the monothiol glutaredoxin family.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Taylor WR. Evolutionary transitions in protein fold space. Current opinion in structural biology. 2007;17:354–361. - PubMed
    1. Gancedo C, Flores C-L. Moonlighting proteins in yeasts. Microbiology and molecular biology reviews: MMBR. 2008;72:197–210. table of contents. - PMC - PubMed
    1. Commichau FM, Stulke J. Trigger enzymes: bifunctional proteins active in metabolism and in controlling gene expression. Molecular microbiology. 2008;67:692–702. - PubMed
    1. Reeves GA, Dallman TJ, Redfern OC, Akpor A, Orengo CA. Structural Diversity of Domain Superfamilies in the CATH Database. Journal of Molecular Biology. 2006;360:725–741. This paper, along with reference [5], describe the surprising amount of structural diversity that can arise in proteins that are related evolutionarily as a result of variations functional necessities, such as novel oligomeric states or binding of ligands with different moieties. - PubMed
    1. Andreeva A, Murzin AG. Evolution of protein fold in the presence of functional constraints. Current opinion in structural biology. 2006;16:399–408. - PubMed

Publication types

LinkOut - more resources