Protein Families

BioCodeKb - Bioinformatics Knowledgebase

A protein family is a group of proteins that share a common evolutionary origin, reflected by their related functions and similarities in sequence or structure. Protein families are often arranged into hierarchies, with proteins that share a common ancestor subdivided into smaller, more closely related groups. Currently, over 60,000 protein families have been defined, although ambiguity in the definition of protein family leads different researchers to wildly varying numbers.


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. There is a fairly well developed framework 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 there is no identifiable sequence homology.


According to current consensus, protein families arise in two ways. Firstly, 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. Secondly, 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).


As the total number of sequenced proteins increases and interest expands in proteome analysis, there is an ongoing effort to organize proteins into families and to describe their component domains and motifs. Reliable identification of protein families is critical to phylogenetic analysis, functional annotation, and the exploration of diversity of protein function in a given phylogenetic branch. The Enzyme Function Initiative (EFI) 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.


There are many biological databases that 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

  • SUPERFAMILY: Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms

  • SCOP and CATH: classifications of protein structures into superfamilies, families and domains


There are a number of well-known signature databases in the public domain that use some methods to produce diagnostic signatures for protein families, domains, repeats, active sites, binding sites and post-translational modifications. These include PROSITE, PRINTS-S, SMART, TIGRFAMs and Blocks.

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