Calmodulin

Calmodulin, or calmodulin-modulated protein. calciumis a calcium-binding protein found in the cytoplasm of all cells eukaryotes. It interacts with many other proteins in the cell and acts as a regulator or molecule effector molecule in a wide variety of cellular functions. These functions include things as diverse as the regulation of the cell cycleintracellular signalling, the fertilisation and muscle contraction. Calmodulin belongs to a family of proteins along with troponin C, another essential calcium-binding protein involved in muscle contraction. Calmodulin is an essential protein; mutations in any of the genes encoding calmodulin or damage to calmodulin binding sites are often lethal.

Structure of calmodulin

Calmodulin is a protein made up of 148 residues of amino acids. It is encoded by multiple genes; in humans: CALM1, CALM2 and CALM3 which are located on chromosomes 14, 2 and 19, respectively. Calcodulin forms two globular domains connected by a flexible central linker. Each domain binds two calcium ions in the EF hand motifs, a ubiquitous motif in calcium-binding proteins, so that calmodulin can bind to a total of four Ca ²⁺. The calcium binding sites are 12 amino acids long and contain many polar or negatively charged amino acid residues, such as aspartate, glutamate and asparagine. The side chains of these amino acids form ionic bonds with the Ca ²⁺ions. Other amino acid residues with side chains rich in oxygen also attract calcium cations. This promotes binding even at very low concentrations of Ca ²⁺.

When calcium binds to calmodulin, a helix-loop-helix is formed along the backbone and a conformational change occurs. This conformational change, together with the flexibility of the protein due to the flexible connecting linker, allows calmodulin to interact with and bind to a wide variety of other proteins.

This figure shows the structure of calmodulin with four calcium ions attached.

Calmodulin function

Calcodulin is a ubiquitous regulatory protein involved in many calcium-mediated processes. When Ca ^{2+ is} binds to calmodulin, forms the Ca ²⁺ / calmodulin which then interacts with other proteins in the cell. These proteins are enzymes and effector proteins involved in a variety of cellular and physiological processes. The Ca ²⁺ / calmodulin can also regulate processes directly.

One of the functions of the Ca ²⁺ / calmodulin is to activate calcium pumps. These pumps remove calcium from the cytoplasm by pumping it out of the cell or storing it in the endoplasmic reticulum. By controlling the amount of calcium in the cell, downstream responses are regulated.

Other examples of the function of the Ca ²⁺ / calmodulin include binding to Ca ²⁺ / calmodulin kinases (CAMKs) such as myosin light chain kinase. This binding allows CAMKs to phosphorylate effector proteins by transferring phosphates from ATP to serine and threonine residues in the receptor proteins. These proteins then activate downstream processes such as intracellular signalling, contractions of the muscle smooth muscle, the synthesis and release of neurotransmitters and hormones, and the regulation of the cell cycle.

This figure shows an example of how calmodulin (CaM) can participate in a complex pathway in a postsynaptic neuron. The pathway shown here is the KEGG pathway in human drug addiction.

Calcium

It is becoming increasingly evident that calcium plays a fundamental role in several physiological processes. When not in use, the concentration gradient of calcium ions between the inside and outside of the cell is very large; the extracellular calcium concentration is about 1 mM while the concentration of free calcium ions inside the cell is less than 0.1 µM. This is probably due to the fact that calcium will readily interact with many proteins.

Most of the calcium in the cell enters through closed calcium channels. It can also be stored in the endoplasmic reticulum. Calcium channels are large transmembrane proteins that allow the passage of ions into the cell when a specific stimulus is met. ligand.