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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 , 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.

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