Sandbox 4465: Difference between revisions

Calmodulin is located and used ubiquitously by cells, but is especially prevalent in brain and muscle tissue. It has also been found human serum, breast milk, urine, and saliva<ref>MacNeil S., Dawson RA., Crocker G., Barton CH., Hanford L., McGurk MR., and Munro DS., (1988). Extracellular calmodulin and its association with epidermal growth factor in normal human body fluids.</ref>. Calmodulin in the cell is mainly localized within organelles and binds to Calcium. Calcium binding then promotes the phosphorylation of protein kinases and activation of other proteins to begin signal transduction for a variety of different pathways, mainly different forms of cell signaling. The phosphorylation of these protein-kinases occurs when Ca2+ reach about 1000 nM and initiates a rapid signaling pathway<ref>doi:10.1038/35036035</ref>.

Calmodulin has a molecular mass of 16 kilodaltons (kD) and it functions along with ryanodine receptor (RyR)<ref>doi: 10.1242/jcs.133454</ref>. CaM consists of 148 amino acid residues and is characterized by a helix-loop-helix binding motif, also known as the EF hand <ref>doi:10.1016/S0006-3495(98)77876-2</ref>. Calmodulin has one subunit with a distinct dumbbell shape in which a linker region joins two globular domains<ref>doi:10.1371/journal.pcbi.1004063</ref>. Calmodulin is known to undergo a conformational change upon binding with a calcium ion in which each lobe transitions from a closed conformation to an open conformation<ref>doi:10.1002/elps.1150110104</ref>. This protein has four major, high-affinity binding sites, as shown by figure 1. The calmodulin binding region has been shown to be a series of hydrophobic amino acids (such as Trp or Leu), hydrophilic amino acids (such as Glu or Asp), and basic amino acids (such as Arg or Lys)<ref>PMID:1737757</ref>. Calmodulin typically wraps around its target, with the two globular domains gripping either side of it (Figure 1). NMR studies clearly show that the connector between the two calcium binding globular domains is flexible even when it is not bound to its target proteins. However, the full range of flexibility can be seen in calmodulin interactions with its target proteins (Figure 1).  

Each end of the globular domains of CaM binds to two Calcium ions, which allows CaM to bind to a total of four Calcium ions. The conformational changes which CaM undergoes allow it to be able to bind more specifically (Figure 1). Calmodulin elicits a pathway signal transduction by activating protein kinases which can then go on to phosphorylate other proteins, or other proteins can directly bind to Calmodulin<ref>doi:10.1128/EC.01.1.119-125.2002</ref>. This would require that the other proteins have a specific binding motif or substrate binding mechanism for Calmodulin (Figure 2). Because there are many different types of binding motifs used by other proteins to interact with Calmodulin, there are no conserved amino acid sequences for CaM binding.EF-hand motifs are a common type of calcium binding motif. These motifs can be characterized as having a helix-loop-helix pattern with 12 sequence residues. Aspartic acid, asparagine, glutamate, and serine are common residues found in this motif. By forming a loop, the motif allows calcium to bind more efficiently and securely (Figure 3). Once inside the binding site, calcium can then induce a conformational change.