Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers [1,2,3,4,5]

This signature pattern includes the complete EF-hand loop as well as the first residue which follows the loop and which seem to always be hydrophobic. Note: positions 1 (X), 3 (Y) and 12 (-Z) are the most conserved. The 6th residue in an EF-hand loop is, in most cases a Gly, but the number of exceptions to this 'rule' has gradually increased, therefore, this signature pattern includes all the different residues which have been shown to exist in this position in functional Ca-binding sites. The pattern is known, in some cases, to miss one of the EF-hand regions in some proteins with multiple EF-hand domains.

1. EF-hands embrace. Trends Biochem. Sci. 4, 514-6
2. Calcium binding and conformational response in EF-hand proteins. Nat. Struct. Biol. 21, 14-7
3. Calcium-binding proteins 1: EF-hands. Nat. Struct. Biol. 2, 297-490
4. Signal transduction versus buffering activity in Ca(2+)-binding proteins. Proteins 1, 239-45
5. Diversity of conformational states and changes within the EF-hand protein superfamily. null 37, 499-507

Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-
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