Abstract
Proteins with EF-hand calcium-binding motifs are essential for many cellular processes, but are also associated with cancer, autism, cardiac arrhythmias, and Alzheimer's, skeletal muscle and neuronal diseases. Functionally, all EF-hand proteins are divided into two groups: (1) calcium sensors, which function to translate the signal to various responses; and (2) calcium buffers, which control the level of free Ca2+ ions in the cytoplasm. The borderline between the two groups is not clear, and many proteins cannot be described as definitive buffers or sensors. Here, we describe two highly-conserved structural motifs found in all known different families of the EF-hand proteins. The two motifs provide a supporting scaffold for the DxDxDG calcium binding loop and contribute to the hydrophobic core of the EF hand domain. The motifs allow more precise identification of calcium buffers and calcium sensors. Based on the characteristics of the two motifs, we could classify individual EF-hand domains into five groups: (1) Open static; (2) Closed static; (3) Local dynamic; (4) Dynamic; and (5) Local static EF-hand domains.
Highlights
Calcium is essential for life [1] and plays at least two major roles in living organisms: structural and regulatory [2,3]
Calcium can act as an extracellular primary messenger, taking on the role of a near-universal signaling molecule recognized by a wide variety of calcium-binding proteins in eukaryotes, prokaryotes and even viruses [2,3,4,5,6]
At the level of the protein structure, calcium may play important structural roles at the molecular level, required for maintaining appropriate conformations of individual proteins, such as at the b-propeller inter-domain interface in integrin a subunits and the homologous domains found in bacteria [7]
Summary
Calcium is essential for life [1] and plays at least two major roles in living organisms: structural and regulatory [2,3]. Many aspects of neuronal activity, ranging from rapid modulation of channel function within a millisecond timescale to long-term switches in gene expression, are controlled by changes in the cytosolic calcium concentration. All of these various actions of Ca2+ ions are mediated by calcium-binding proteins that, in turn, interact with their target proteins. All EF-hand -containing proteins are divided into two groups: (1) Calcium sensors that include calmodulin, recoverin, and most of the other known EF-hand proteins, which function to translate the signal of a change in concentration of Ca2+ ions to various responses; and (2) Calcium buffers, represented by parvalbumin, calbindin D9k, calbindin D28k and calretinin that serve to modulate calcium signals as they bind free Ca2+ ions [17]. Each structural motif incorporates a cluster of three amino acids whose structure and structural rearrangement on calcium binding can serve to classify EF-hand domains into five separate classes
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