Pfam

The general purpose of the Pfam database is to provide a complete and accurate classification of protein families and domains.[5] Originally, the rationale behind creating the database was to have a semi-automated method of curating information on known protein families to improve the efficiency of annotating genomes.[6] The Pfam classification of protein families has been widely adopted by biologists because of its wide coverage of proteins and sensible naming conventions.[7]

It is used by experimental biologists researching specific proteins, by structural biologists to identify new targets for structure determination, by computational biologists to organise sequences and by evolutionary biologists tracing the origins of proteins.[8] Early genome projects, such as human and fly used Pfam extensively for functional annotation of genomic data.[9][10][11]

The Pfam website allows users to submit protein or DNA sequences to search for matches to families in the database. If DNA is submitted, a six-frame translation is performed, then each frame is searched.[12] Rather than performing a typical BLAST search, Pfam uses profile hidden Markov models, which give greater weight to matches at conserved sites, allowing better remote homology detection, making them more suitable for annotating genomes of organisms with no well-annotated close relatives.[13]

Pfam has also been used in the creation of other resources such as iPfam, which catalogs domain-domain interactions within and between proteins, based on information in structure databases and mapping of Pfam domains onto these structures.[14]

For each family in Pfam one can:

• View a description of the family
• Look at multiple alignments
• View protein domain architectures
• Examine species distribution
• Follow links to other databases
• View known protein structures

Entries can be of several types: family, domain, repeat or motif. Family is the default class, which simply indicates that members are related. Domains are defined as an autonomous structural unit or reusable sequence unit that can be found in multiple protein contexts. Repeats are not usually stable in isolation, but rather are usually required to form tandem repeats in order to form a domain or extended structure. Motifs are usually shorter sequence units found outside of globular domains.[9]

The descriptions of Pfam families are managed by the general public using Wikipedia (see History).

As of release 29.0, 76.1% of protein sequences in UniprotKB matched to at least one Pfam domain.[15]

Pfam was founded in 1995 by Erik Sonhammer, Sean Eddy and Richard Durbin as a collection of commonly occurring protein domains that could be used to annotate the protein coding genes of multicellular animals.[6] One of its major aims at inception was to aid in the annotation of the C. elegans genome.[6] The project was partly driven by the assertion in ‘One thousand families for the molecular biologist’ by Cyrus Chothia that there were around 1500 different families of proteins and that the majority of proteins fell into just 1000 of these.[5][19] Counter to this assertion, the Pfam database currently contains 16,306 entries corresponding to unique protein domains and families. However, many of these families contain structural and functional similarities indicating a shared evolutionary origin (see Clans).[5]

A major point of difference between Pfam and other databases at the time of its inception was the use of two alignment types for entries: a smaller, manually checked seed alignment, as well as a full alignment built by aligning sequences to a profile hidden Markov model built from the seed alignment. This smaller seed alignment was easier to update as new releases of sequence databases came out, and thus represented a promising solution to the dilemma of how to keep the database up to date as genome sequencing became more efficient and more data needed to be processed over time. A further improvement to the speed at which the database could be updated came in version 24.0, with the introduction of HMMER3, which is ~100 times faster than HMMER2 and more sensitive.[8]

Because the entries in Pfam-A do not cover all known proteins, an automatically generated supplement was provided called Pfam-B. Pfam-B contained a large number of small families derived from clusters produced by an algorithm called ADDA.[20] Although of lower quality, Pfam-B families could be useful when no Pfam-A families were found. Pfam-B was discontinued as of release 28.0,[21] then reintroduced in release 33.1 using a new clustering algorithm, MMSeqs2.[22]

Pfam was originally hosted on three mirror sites around the world to preserve redundancy. However between 2012-2014, the Pfam resource was moved to EMBL-EBI, which allowed for hosting of the website from one domain (xfam.org), using duplicate independent data centres. This allowed for better centralisation of updates, and grouping with other Xfam projects such as Rfam, TreeFam, iPfam and others, whilst retaining critical resilience provided by hosting from multiple centres.[23]

Pfam has undergone a substantial reorganisation over the last two years to further reduce manual effort involved in curation and allow for more frequent updates.[15]

• List of biological databases
• Rfam Database for conserved non-coding RNA families
• TreeFam Database of phylogenetic trees of animal genes
• TrEMBL Database performing an automated protein sequence annotation
• InterPro Integration of protein domain and protein family databases
• PDBfam — thorough assignment of Pfam domains to sequences in the Protein Data Bank (PDB)[24][25]

• Pfam - Protein family database at EBI UK
• iPfam - Interactions of Pfam domains in PDB
• PDBfam - Assignments of Pfam domains to sequences in the PDB at Fox Chase Cancer Center USA
• PlantTFDB - The family assignment rules for plant transcription factors based on Pfam domains