A protein family is a group of evolutionarily related proteins. 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 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 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), 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, and cytochrome c 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.