EFHand

The EF-hand is a widely distributed calcium-binding motif found in many proteins that regulate cellular processes. It consists of a short, helix-loop-helix structure about 12 amino acids long, flanked by two α-helices named the E and F helices. The loop contains conserved residues that coordinate a Ca2+ ion, typically using several oxygen ligands from side chains and the protein backbone, producing a characteristic geometry around the bound calcium.

In proteins, EF-hand domains frequently occur in tandem, creating multi-site calcium-binding modules. Prominent examples include calmodulin and troponin C, each containing four EF-hands, and parvalbumin, which has multiple EF-hands with varying calcium-binding properties. Some EF-hands bind Ca2+ strongly and regulate activity, while others are degenerate and do not bind calcium.

Functionally, binding of Ca2+ induces conformational changes in EF-hand–containing proteins. These changes expose hydrophobic surfaces or alter interaction interfaces, enabling binding to target proteins and modulating signaling pathways, muscle contraction, neurotransmitter release, enzyme activity, and gene expression. The EF-hand motif thus acts as a calcium sensor and regulator across diverse cellular contexts.

Evolution and diversity: EF-hands are present in a wide range of eukaryotes and in some bacteria. The number of functional EF-hands in a protein, along with their calcium-binding affinity and kinetics, shapes the protein’s role in calcium signaling.

Applications: The modular nature of EF-hands makes them useful in protein engineering and biosensing. EF-hand motifs have inspired calcium indicators and sensors that visualize Ca2+ dynamics in cells.