REVIEW: EF-Hand Calcium-Binding Motif: Novel Structural and Functional Insights

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Konstantin A. Denessiouk¹, Evgeny A. Permyakov¹, Alexander I. Denesyuk¹, and Sergey E. Permyakov^1,a*

¹Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia

^* To whom correspondence should be addressed.

Received: April 9, 2026; Revised: July 7, 2026; Accepted: August 10, 2026

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The EF-hand motif is one of the most widespread calcium-binding protein motifs in nature, mediating calcium signaling across a variety of biological processes. While structural and functional properties of the individual proteins within the EF-hand superfamily are well studied, general principles governing organization and function of these proteins are only now being elucidated. This review examines some of these emerging patterns, including recently discovered structural elements of the EF-hand motif (EF-hand zone, one-residue and three-residue units, local “Clamp” units, and “black” and “gray” clusters). Additionally, we discuss the ability of certain EF-hand proteins to recognize a broad spectrum of protein targets, as well as their zinc-binding properties. New structural data on the EF-hand domain allow proposing a structural-functional classification for the proteins in this family. Furthermore, tendency of some EF-hand proteins toward promiscuity and zinc binding significantly expands their functional importance.

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KEY WORDS: three-dimensional structure, protein structure, motif, cluster, protein–ligand interactions, protein–protein interactions, promiscuity, calcium, zinc, calcium-binding proteins, EF-hand, S100 proteins, calmodulin

DOI: 10.1134/S0006297926601115

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