Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: two ways to promote multifunctionality

Abstract

Calcium signaling pathways control a variety of cellular events such as gene transcription, protein phosphorylation, nucleotide metabolism, and ion transport. These pathways often involve a large number of calcium-binding proteins collectively known as the calmodulin or EF-hand protein superfamily. Many EF-hand proteins undergo a large conformational change upon binding to Ca(2+) and target proteins. All members of the superfamily share marked sequence homology and similar structural features required to sense Ca(2+). Despite such structural similarities, the functional diversity of EF-hand calcium-binding proteins is extraordinary. Calmodulin itself can bind >300 different proteins, and the many members of the neuronal calcium sensor and S100 protein families collectively recognize a largely different set of target proteins. Recent biochemical and structural studies of many different EF-hand proteins highlight remarkable similarities and variations in conformational responses to the common ligand Ca(2+) and their respective cellular targets. In this review, we examine the essence of molecular recognition activities and the mechanisms by which calmodulin superfamily proteins control a wide variety of Ca(2+) signaling processes.

Fig. 1.

Space-filling structures of NCS (A) and S100 (B) proteins. Positive, negative, and hydrophobic residues on the protein surface are highlighted in blue, pink, and yellow, respectively. Ribbon diagram of bound target helices are shown in red. Conserved hydrophobic residues implicated in target recognition are labeled. Atomic coordinates are available from the Protein Data Bank: 1rec (recoverin), 1bjf (neurocalcin), 1g8i (frequenin), 1s6c (KChIP1), 1bt6 (S100A10), 1dt7 (S100B), and 1e8a (S100A12).

Fig. 2.

Structure and target recognition by calmodulin. (A) Superposition of selected NMR structures of apo-calmodulin (Protein Data Bank entry 1dmo). (B) Space-filling representation of hydrophobic target binding sites (yellow) flanked by surrounding methionine residues (orange). (C) Main-chain ribbon diagrams of calmodulin (yellow) bound to the target proteins myosin light chain kinase (MLCK), SK channel, GAD, and EF (red). Bound Ca²⁺ ions are shown in blue.