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.

6. 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.

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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

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

15. 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.

16. 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.

17. Reference.
Tortora Gerard J. & Derrickson Bryan,” PRINCIPLES OF
ANATOMY AND PHYSIOLOGY” , 12th 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