Calmodulin and its regulatory role

Calmodulin is a low molecular weight, acidic, calcium binding protein .
It is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells.
It is an intermediate target of the secondary messenger Ca 2+.
The binding of calcium is required for the activation of calmodulin

1. Calmodulin and its regulatory roles. By, Nelson Prashanth D'Souza. M.Sc. Biochemistry Mangalore University

2. Introduction. Calmodulin is a low molecular weight, acidic, calcium binding protein . It is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intermediate target of the secondary messenger Ca 2+. The binding of calcium is required for the activation of calmodulin.

3. Structure. Calmodulin is a small, highly conserved protein that is 148 amino acid long. The protein has two approximately symmetrical globular domains each containing a pair of EF-hand motifs (the N- and C-domain) separated by a flexible linker region for a total of four Ca2+ binding sites.

4. Each EF-hand motif allows calmodulin to sense intracellular calcium levels by binding up to four Ca2+ ions. Calcium ion binding regions are found in the following positions in the sequence of amino acids: 21-32, 57-68, 94-105 and 130-141 Each region that calcium binds to is exactly 12 amino acids long. The first two regions (21-32 and 57-68) are on one side of the linker region the other two (94-105 and 130-141) are on the other side .

5. Similarity to Troponin C Calmodulin's structure is very similar to the structure of Troponin C . Troponin C, like Calmodulin, has two globular domains that are connected by a linker region. Troponin C and Calmodulin differ in the length of the linker region; the linker region of Calmodulin is smaller than that of Troponin C. They have similar structures but their functions are very different. Troponin C has a very specific function ultimately causing a contraction in skeletal muscles.

6. Calmodulin, evolved to bind a wider variety of target proteins, allowing it to play a role in many physiological events .

7. Mechanism Of Action An essential phase in the mechanism of activation of enzymes by calmodulin is a conformational change induced in calmodulin by binding of Ca2+. This results in exposure of a sites which can interact with the target enzyme. Upon binding Ca2+, calmodulin becomes a more compact, globular structure and a hydrophobic site becomes exposed on the surface of the molecule.

8. This hydrophobic site involved in the interaction of calmodulin with its target proteins. calmodulin activates most of its target enzyme. *Denotes an active conformation. CaM = calmodulin. TE = target enzyme.

9. Regulatory Role of Calmodulin. Role in smooth muscle contraction . The initiating stimulus for most smooth muscle contraction is an increase in intracellular calcium ions. This increase can be caused in different types of smooth muscle by nerve stimulation of the smooth muscle fiber, hormonal stimulation, stretch of the fiber, or even change in the chemical environment of the fiber.

10. Smooth muscle does not contain troponin, the regulatory protein that is activated by calcium ions to cause skeletal muscle contraction. Smooth muscle contraction is activated by an entirely different mechanism. In Place of troponin smooth muscle cells contain a large amount of another regulatory protein called calmodulin. This protein is similar to troponin, it is different in the manner in which it initiates contraction.

11. Calmodulin binds to calcium in the cytosol. After calmodulin activate the enzyme called myosin light chain kinase. This enzyme uses ATP to add a phosphate group to a portion of the myosin head. Myosin head bind to actin and contraction can occur.

12. Other Calmodulin Regulated processes. Insulin secretion from pancreatic B cells. Pancreatic enzyme secretion. Intestinal secretion. Platelet release reaction. Platelet adhesion end plug formation.

13. Summary. Calmodulin is a multifunctional intermediate calcium binding protein expressed in all eukaryotic cells. The binding of calcium is required for the activation of calmodulin. It is a small, highly conserved protein that is 148 amino acid long. It has two approximately symmetrical globular domains each containing a pair of EF-hand motifs separated by a flexible linker region.

14. Calmodulin structure is similar to the structure of troponin C but differ in the length of linker region and their function Calmodulin activates most of its target enzymes. Calmodulin plays an important role in excitation contraction (EC) coupling and the initiation of the cross-bridge cycling in smooth muscle, ultimately causing smooth muscle contraction. Other calmodulin-regulated processes are Insulin secretion from pancreatic B cells, Pancreatic enzyme secretion, Intestinal secretion, Platelet release reaction and Platelet adhesion end plug formation.

15. Reference. Tortora Gerard J. & Derrickson Bryan,” PRINCIPLES OF ANATOMY AND PHYSIOLOGY” , 12 th edition ,2009. Hall. J.E. Guyton and Hall “TEXTBOOK OF MEDICAL PHYSIOLOGY”. 12th ed. Saunders, Elsevier Inc., 2011 . Wikipedia : https://en.wikipedia.org/wiki/Calmodulin www.ncbi.nlm.nih.gov/pubmed/6307499

16. thank you