PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification

Abstract

The PANTHER database was designed for high-throughput analysis of protein sequences. One of the key features is a simplified ontology of protein function, which allows browsing of the database by biological functions. Biologist curators have associated the ontology terms with groups of protein sequences rather than individual sequences. Statistical models (Hidden Markov Models, or HMMs) are built from each of these groups. The advantage of this approach is that new sequences can be automatically classified as they become available. To ensure accurate functional classification, HMMs are constructed not only for families, but also for functionally distinct subfamilies. Multiple sequence alignments and phylogenetic trees, including curator-assigned information, are available for each family. The current version of the PANTHER database includes training sequences from all organisms in the GenBank non-redundant protein database, and the HMMs have been used to classify gene products across the entire genomes of human, and Drosophila melanogaster. The ontology terms and protein families and subfamilies, as well as Drosophila gene c;assifications, can be browsed and searched for free. Due to outstanding contractual obligations, access to human gene classifications and to protein family trees and multiple sequence alignments will temporarily require a nominal registration fee. PANTHER is publicly available on the web at http://panther.celera.com.

Figure 1

Browsing the PANTHER database by biological functions. (A) Selection of biological processes under lipid, fatty acid and steroid metabolism (note that categories can be independently selected/deselected, so, for example, steroid metabolism has been deselected). (B) Retrieval of protein families and subfamilies assigned by curators to the selected functional categories. (C) Retrieval of a list of human genes encoding proteins that match the selected family and subfamily HMMs.

Figure 1

Browsing the PANTHER database by biological functions. (A) Selection of biological processes under lipid, fatty acid and steroid metabolism (note that categories can be independently selected/deselected, so, for example, steroid metabolism has been deselected). (B) Retrieval of protein families and subfamilies assigned by curators to the selected functional categories. (C) Retrieval of a list of human genes encoding proteins that match the selected family and subfamily HMMs.

Figure 1

Browsing the PANTHER database by biological functions. (A) Selection of biological processes under lipid, fatty acid and steroid metabolism (note that categories can be independently selected/deselected, so, for example, steroid metabolism has been deselected). (B) Retrieval of protein families and subfamilies assigned by curators to the selected functional categories. (C) Retrieval of a list of human genes encoding proteins that match the selected family and subfamily HMMs.

Figure 2

The PANTHER multiple sequence alignment view, highlighting globally conserved positions (black and gray), and subfamily-specific conservation patterns that may indicate residues important for functional specificity (red). Pfam domains are shown as blue bars, one for each subfamily.

Figure 3

The PANTHER tree-attribute view for verifying curation. (A) The ‘collapsed view’, showing the curator-defined subfamilies and ontology associations. (B) The ‘expanded view’, showing all of the constituent sequences and their annotations.

Figure 3

The PANTHER tree-attribute view for verifying curation. (A) The ‘collapsed view’, showing the curator-defined subfamilies and ontology associations. (B) The ‘expanded view’, showing all of the constituent sequences and their annotations.

Figure 4

Examples of PANTHER subfamilies capturing functional divergence. (A) Laminin-related proteins have divergent domain structures (which correlates with divergence within the shared laminin domain), while (B) Secretin-related GPCRs have divergent sequences within a common domain. Both cases can generally be modelled using subfamily HMMs.

Figure 4

Examples of PANTHER subfamilies capturing functional divergence. (A) Laminin-related proteins have divergent domain structures (which correlates with divergence within the shared laminin domain), while (B) Secretin-related GPCRs have divergent sequences within a common domain. Both cases can generally be modelled using subfamily HMMs.