Abstract
Calmodulin (CaM) is an important intracellular protein that binds Ca2+ and functions as a critical second messenger involved in numerous biological activities through extensive interactions with proteins and peptides. CaM’s ability to adapt to binding targets with different structures is related to the flexible central helix separating the N- and C-terminal lobes, which allows for conformational changes between extended and collapsed forms of the protein. CaM-binding targets are most often identified using prediction algorithms that utilize sequence and structural data to predict regions of peptides and proteins that can interact with CaM. In this review, we provide an overview of different CaM-binding proteins, the motifs through which they interact with CaM, and shared properties that make them good binding partners for CaM. Additionally, we discuss the historical and current methods for predicting CaM binding, and the similarities and differences between these methods and their relative success at prediction. As new CaM-binding proteins are identified and classified, we will gain a broader understanding of the biological processes regulated through changes in Ca2+ concentration through interactions with CaM.
Highlights
Calmodulin (CaM) is an intracellular Ca2+-binding protein (CaBP) in eukaryotic systems, which functions as a second messenger that regulates myriad vital biological processes through interactions with more than 300 target proteins and peptides
Methods for predicting CaM-binding proteins have evolved over time, based on data obtained from prior studies, and in conjunction with the development of new algorithms and computational approaches to prediction problems
For classifying proteins as CaM-binding target proteins or otherwise, the use of a binary classification system is implemented. This system generally uses a 2 × 2 matrix consisting of true positives (TP), false positives (FP), true negatives (TN), and false negatives (FN)
Summary
Calmodulin (CaM) is an intracellular Ca2+-binding protein (CaBP) in eukaryotic systems, which functions as a second messenger that regulates myriad vital biological processes through interactions with more than 300 target proteins and peptides. The EF-hand motif, exhibiting pentagonal-bipyramidal geometry, includes a highly-conserved sequence of 12 amino acid residues, identified by relative positions 1–12 Six of these provide oxygen atoms as the preferred ligands for coordination of Ca2+ ions [5] from side chains of residues in relative positions 1, 3, 5, and 12 [6], with oxygen from a carbonyl group in position 7. It has been experimentally verified that the extended helix has a propensity to be inherently disordered, increasing the overall flexibility of the protein, and allowing CaM to achieve different conformational states in its interactions with other peptides (Figure 1C–I) [9]. It has been experimentally verified that the extended helix has a propensity to be inherently disordered, increasing the overall flexibility of the protein, and allowing CaM to achieve different conformati2oonf a26l states in its interactions with other peptides (Figures 1C–I) [9]. Historical and current methods for predicting CaM binding, and the similarities and differences between these methods and their relative success at prediction, will be discussed
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