Pfam

Pfam is a database of protein families that includes their

annotations and multiple sequence alignments generated using
Pfam
hidden Markov models.[1][2][3] The most recent version, Pfam
35.0, was released in November 2021 and contains 19,632
families.[4] Content
Description The Pfam
Uses database
provides
The general purpose of the Pfam database is to provide a complete alignments and
and accurate classification of protein families and domains.[5] hidden Markov
Originally, the rationale behind creating the database was to have a models for
semi-automated method of curating information on known protein
protein domains.
families to improve the efficiency of annotating genomes.[6] The
Pfam classification of protein families has been widely adopted by Data types Protein families
biologists because of its wide coverage of proteins and sensible captured
naming conventions.[7] Organisms all

It is used by experimental biologists researching specific proteins, Contact

by structural biologists to identify new targets for structure Research center EBI
determination, by computational biologists to organise sequences Primary citation PMID 19920124
and by evolutionary biologists tracing the origins of proteins.[8] (https://pubmed.
Early genome projects, such as human and fly used Pfam
ncbi.nlm.nih.gov/
extensively for functional annotation of genomic data.[9][10][11]
19920124)
The Pfam website allows users to submit protein or DNA Access
sequences to search for matches to families in the database. If Data format Stockholm
DNA is submitted, a six-frame translation is performed, then each
format
frame is searched.[12] Rather than performing a typical BLAST
search, Pfam uses profile hidden Markov models, which give Website www.ebi.ac.uk
greater weight to matches at conserved sites, allowing better /interpro (http://
remote homology detection, making them more suitable for www.ebi.ac.uk/in
annotating genomes of organisms with no well-annotated close terpro)
relatives.[13] Download URL FTP (http://ftp.e
Pfam has also been used in the creation of other resources such as bi.ac.uk/pub/dat
iPfam, which catalogs domain-domain interactions within and abases/Pfam)
between proteins, based on information in structure databases and Miscellaneous
mapping of Pfam domains onto these structures.[14]
License GNU Lesser
General Public
Features License
Version 35.0
For each family in Pfam one can:
Bookmarkable yes
View a description of the family entities
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]

Creation of new entries

New families come from a range of sources, primarily the PDB and analysis of complete proteomes to find
genes with no Pfam hit.[16]

For each family, a representative subset of sequences are aligned into a high-quality seed alignment.
Sequences for the seed alignment are taken primarily from pfamseq (a non-redundant database of reference
proteomes) with some supplementation from UniprotKB.[15] This seed alignment is then used to build a
profile hidden Markov model using HMMER. This HMM is then searched against sequence databases, and
all hits that reach a curated gathering threshold are classified as members of the protein family. The resulting
collection of members is then aligned to the profile HMM to generate a full alignment.

For each family, a manually curated gathering threshold is assigned that maximises the number of true
matches to the family while excluding any false positive matches. False positives are estimated by
observing overlaps between Pfam family hits that are not from the same clan. This threshold is used to
assess whether a match to a family HMM should be included in the protein family. Upon each update of
Pfam, gathering thresholds are reassessed to prevent overlaps between new and existing families.[16]

Domains of unknown function

Domains of unknown function (DUFs) represent a growing fraction of the Pfam database. The families are
so named because they have been found to be conserved across species, but perform an unknown role.
Each newly added DUF is named in order of addition. Names of these entries are updated as their functions
are identified. Normally when the function of at least one protein belonging to a DUF has been determined,
the function of the entire DUF is updated and the family is renamed. Some named families are still domains
of unknown function, that are named after a representative protein, e.g. YbbR. Numbers of DUFs are
expected to continue increasing as conserved sequences of unknown function continue to be identified in
sequence data. It is expected that DUFs will eventually outnumber families of known function.[16]

Clans

Over time both sequence and residue coverage have increased, and as families have grown, more
evolutionary relationships have been discovered, allowing the grouping of families into clans.[8] Clans were
first introduced to the Pfam database in 2005. They are groupings of related families that share a single
evolutionary origin, as confirmed by structural, functional, sequence and HMM comparisons.[5] As of
release 29.0, approximately one third of protein families belonged to a clan.[15] This portion has grown to
around three-fourths by 2019 (version 32.0).[17]

To identify possible clan relationships, Pfam curators use the Simple Comparison Of Outputs Program
(SCOOP) as well as information from the ECOD database.[17] ECOD is a semi-automated hierarchical
database of protein families with known structures, with families that map readily to Pfam entries and
homology levels that usually map to Pfam clans.[18]

History
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 and 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]

Community curation

Curation of such a large database presented issues in terms of keeping up with the volume of new families
and updated information that needed to be added. To speed up releases of the database, the developers
started a number of initiatives to allow greater community involvement in managing the database.
A critical step in improving the pace of updating and improving entries was to open up the functional
annotation of Pfam domains to the Wikipedia community in release 26.0.[16] For entries that already had a
Wikipedia entry, this was linked into the Pfam page, and for those that did not, the community were invited
to create one and inform the curators, in order for it to be linked in. It is anticipated that while community
involvement will greatly improve the level of annotation of these families, some will remain insufficiently
notable for inclusion in Wikipedia, in which case they will retain their original Pfam description. Some
Wikipedia articles cover multiple families, such as the Zinc finger article. An automated procedure for
generating articles based on InterPro and Pfam data has also been implemented, which populates a page
with information and links to databases as well as available images, then once an article has been reviewed
by a curator it is moved from the Sandbox to Wikipedia proper. In order to guard against vandalism of
articles, each Wikipedia revision is reviewed by curators before it is displayed on the Pfam website. Almost
all cases of vandalism have been corrected by the community before they reach curators, however.[16]

Pfam is run by an international consortium of three groups. In the earlier releases of Pfam, family entries
could only be modified at the Cambridge, UK site, limiting the ability of consortium members to contribute
to site curation. In release 26.0, developers moved to a new system that allowed registered users anywhere
in the world to add or modify Pfam families.[16]

See also
List of biological databases
PANDIT, a biological database covering protein domains
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 (http://dunbrack2.fccc.edu/protcid/pdbfam) — thorough assignment of Pfam
domains to sequences in the Protein Data Bank (PDB)[24][25]

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External links
Pfam (https://www.ebi.ac.uk/interpro/) - Protein family database at EMBL-EBI, UK
PDBfam (http://dunbrack2.fccc.edu/protcid/pdbfam/) - Assignments of Pfam domains to
sequences in the PDB at Fox Chase Cancer Center, USA

Retrieved from "https://en.wikipedia.org/w/index.php?title=Pfam&oldid=1166578716"