A protein family is a group of
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
arily related
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s. In many cases, a protein family has a corresponding
gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be confused with
family
Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Idea ...
as it is used in taxonomy.
Proteins in a family descend from a common ancestor and typically have similar
three-dimensional structures, functions, and significant
sequence similarity. The most important of these is sequence similarity (usually amino-acid sequence), since it is the strictest indicator of homology and therefore the clearest indicator of common ancestry. A fairly well developed framework exists for evaluating the significance of similarity between a group of sequences using
sequence alignment methods. Proteins that do not share a common ancestor are very unlikely to show statistically significant sequence similarity, making sequence alignment a powerful tool for identifying the members of protein families. Families are sometimes grouped together into larger
clades
A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English te ...
called
superfamilies based on structural and mechanistic similarity, even if no identifiable sequence homology is seen.
Currently, over 60,000 protein families have been defined,
although ambiguity in the definition of "protein family" leads different researchers to highly varying numbers.
Terminology and usage
As with many biological terms, the use of protein family is somewhat context dependent; it may indicate large groups of proteins with the lowest possible level of detectable sequence similarity, or very narrow groups of proteins with almost identical sequence, function, and three-dimensional structure, or any kind of group in between. To distinguish between these situations, the term
protein superfamily is often used for distantly related proteins whose relatedness is not detectable by sequence similarity, but only from shared structural features.
Other terms, such as protein class, group, clan, and subfamily, have been coined over the years, but all suffer similar ambiguities of usage. A common usage is that superfamilies' (
structural homology) contain families (
sequence homology
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a ...
), which contain
subfamilies. Hence, a superfamily, such as the
PA clan of proteases, has far lower sequence conservation than one of the families it contains, the C04 family. an exact definition is unlikely to be agreed upon and to it is up to the reader to discern exactly how these terms are being used in a particular context.
Protein domains and motifs
The concept of protein family was conceived at a time when very few protein structures or sequences were known; at that time, primarily small, single-domain proteins such as
myoglobin,
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...
, and
cytochrome c
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
were structurally understood. Since that time, many proteins were found to comprise multiple independent structural and functional units or
domains. Due to evolutionary
shuffling, different domains in a protein have evolved independently. This has led, in recent years, to a focus on families of protein domains. A number of online resources are devoted to identifying and cataloging such domains.
Regions of each protein have differing functional constraints (features critical to the structure and function of the protein). For example, the
active site of an enzyme requires certain amino-acid residues to be precisely oriented in three dimensions. A protein–protein binding interface, though, may consist of a large surface with constraints on the
hydrophobicity or polarity of the amino-acid residues. Functionally constrained regions of proteins evolve more slowly than unconstrained regions such as surface loops, giving rise to discernible blocks of conserved sequence when the sequences of a protein family are compared (see
multiple sequence alignment). These blocks are most commonly referred to as motifs, although many other terms are used (blocks, signatures, fingerprints, etc.). Again, many online resources are devoted to identifying and cataloging protein motifs.
Evolution of protein families
According to current consensus, protein families arise in two ways. First, the separation of a parent species into two genetically isolated descendent species allows a gene/protein to independently accumulate variations (
mutations) in these two lineages. This results in a family of
orthologous proteins, usually with conserved sequence motifs. Second, a gene duplication may create a second copy of a gene (termed a
paralog). Because the original gene is still able to perform its function, the duplicated gene is free to diverge and may acquire new functions (by random mutation). Certain gene/protein families, especially in
eukaryotes, undergo extreme expansions and contractions in the course of evolution, sometimes in concert with whole
genome duplication
Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contains ...
s. This expansion and contraction of protein families is one of the salient features of
genome evolution
Genome evolution is the process by which a genome changes in structure (sequence) or size over time. The study of genome evolution involves multiple fields such as structural analysis of the genome, the study of genomic parasites, gene and ancient ...
, but its importance and ramifications are currently unclear.
Use and importance of protein families
As the total number of sequenced proteins increases and interest expands in
proteome analysis, an effort is ongoing to organize proteins into families and to describe their component domains and motifs. Reliable identification of protein families is critical to
phylogenetic
In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups ...
analysis, functional annotation, and the exploration of diversity of protein function in a given phylogenetic branch. The
Enzyme Function Initiative
The Enzyme Function Initiative (EFI) is a large-scale collaborative project aiming to develop and disseminate a robust strategy to determine enzyme function through an integrated sequence–structure-based approach. The project was funded in May ...
is using protein families and superfamilies as the basis for development of a sequence/structure-based strategy for large scale functional assignment of enzymes of unknown function.
The algorithmic means for establishing protein families on a large scale are based on a notion of similarity. Most of the time, the only similarity with access to is sequence similarity.
Protein family resources
Many
biological databases record examples of protein families and allow users to identify if newly identified proteins belong to a known family. Here are a few examples:
*
Pfam - Protein families database of alignments and HMMs
*
PROSITE - Database of protein domains, families and functional sites
*
PIRSF - SuperFamily Classification System
* PASS2 - Protein Alignment as Structural Superfamilies v2 - PASS2@NCBS
*
SUPERFAMILY
SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
- Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
*
SCOP and
CATH
The CATH Protein Structure Classification database is a free, publicly available online resource that provides information on the evolutionary relationships of protein domains. It was created in the mid-1990s by Professor Christine Orengo and coll ...
- classifications of protein structures into superfamilies, families and domains
Similarly, many database-searching algorithms exist, for example:
*
BLAST - DNA sequence similarity search
*
BLASTp - Protein sequence similarity search
*
OrthoFinder
OrthoFinder is a command-line software tool for comparative genomics. OrthoFinder determines the correspondence between genes in different organisms (also known as orthology analysis). This correspondence provides a framework for understanding ...
a fast, scalable and accurate method for clustering proteins into families (orthogroups)
See also
*
Gene family
*
Genome annotation
*
Sequence clustering In bioinformatics, sequence clustering algorithms attempt to group biological sequences that are somehow related. The sequences can be either of genomic, " transcriptomic" ( ESTs) or protein origin.
For proteins, homologous sequences are typicall ...
Protein families
References
External links
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{{DEFAULTSORT:Protein Family
Bioinformatics
Protein classification
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