Calmodulin-binding proteins

Protein family

Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit",[1] where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.

Examples include:

* Gap-43 protein (presynaptic)
* Neurogranin (postsynaptic)
* Caldesmon

## Ca2+ Activation

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A variety of different ions, including Calcium (Ca2+), play a vital role in the regulation of cellular functions. Calmodulin, a Calcium-binding protein, that mediates Ca2+ signaling is involved in all types of cellular mechanisms, including metabolism, synaptic plasticity, nerve growth, smooth muscle contraction, etc. Calmodulin allows for a number of proteins to aid in the progression of these pathways using their interactions with CaM in its Ca2+-free or Ca2+-bound state. Proteins each have their own unique affinities for calmodulin, that can be manipulated by Ca2+ concentrations to allow for the desired release or binding to calmodulin that determines its ability to carry out its cellular function. Proteins that get activated upon binding to Ca2+-bound state, include Myosin light-chain kinase, Phosphatase, Ca2+/calmodulin-dependent protein kinase II, etc. Proteins, such as neurogranin that plays a vital role in postsynaptic function, however, can bind to calmodulin in Ca2+-free or Ca2+-bound state via their IQ calmodulin-binding motifs.[2] Since these interactions are exceptionally specific, they can be regulated through post-translational modifications by enzymes like kinases and phosphatases to affect their cellular functions. In the case of neurogranin, it's the synaptic function can be inhibited by the PKC-mediated phosphorylation of its IQ calmodulin-binding motif that impedes its interaction with calmodulin.[3]

Cellular functions can be indirectly regulated by calmodulin, as it acts as a mediator for enzymes that require Ca2+ stimulation for activation. Studies have proven that calmodulin's affinity for Ca2+ increases when it is bound to a calmodulin-binding protein, which allows for it to take on its regulatory role for Ca2+-dependent reactions. Calmodulin, made up of two pairs of EF-hand motifs separated in different structural regions by an extended alpha helical region, that permits it to respond to the changes in the cytosolic concentration of the Ca2+ ions by taking on two distinct conformations, in the inactive Ca2+ unbound state and active Ca2+ bound state. Calmodulin binds to the targeted proteins via their short complementary peptide sequences, causing an “induced fit” conformational change that alters the calmodulin-binding proteins’ activity as desired in response to the second messenger Ca2+ signals that arise due to changes in the intracellular Ca2+ concentrations. These second messenger Ca2+ signals are transduced and integrated to maintain a homeostatic balance of the Ca2+ ions.[4]

## GAP-43 Protein

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Found in the nervous system, GAP-43 is a growth-associated protein (GAP) expressed in high levels during presynaptic developmental and regenerative axonal growth. As a major growth cone component, an increase in GAP-43 concentrations delays the process of axonal growth cones evolving into stable synaptic terminals. All GAP-43 proteins share a completely conserved amino acid sequence that contain a calmodulin-binding domain and a serine residue that can be used to inhibit calmodulin binding upon phosphorylation of Protein kinase C (PKC). By possessing these calmodulin-binding properties, GAP-43 is able to respond to PKC activation and release free calmodulin in desired areas. When there are low levels of Ca2+ concentrations, GAP-43 is able to bind and stabilize the inactive Ca2+-free state of calmodulin, this allows it to absorb and reversibly inactivate the CaM in the growth cones. This binding of the calmodulin to GAP-43 is allowed by the electrostatic interaction between the negatively-charged calmodulin and the positively-charged “pocket” formed in the GAP-43 molecule.[5]

## References

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1. ^ Wang Q, Zhang P, Hoffman L, Tripathi S, Homouz D, Liu Y, Waxham MN, Cheung MS (December 2013). "Protein recognition and selection through conformational and mutually induced fit". Proc Natl Acad Sci U S A. 110 (51): 20545–50\. Bibcode:2013PNAS..11020545W. doi:10.1073/pnas.1312788110. PMC 3870683. PMID 24297894.
2. ^ Hoffman L, Chandrasekar A, Wang X, Putkey JA, Waxham MN (2014-05-23). "Neurogranin alters the structure and calcium binding properties of calmodulin". J Biol Chem. 289 (21): 14644–55\. doi:10.1074/jbc.M114.560656. PMC 4031520. PMID 24713697.
3. ^ Kaleka, Kanwardeep S.; Petersen, Amber N.; Florence, Matthew A.; Gerges, Nashaat Z. (2012-01-23). "Pull-down of Calmodulin-binding Proteins". Journal of Visualized Experiments (59): 3502. doi:10.3791/3502. ISSN 1940-087X. PMC 3462570. PMID 22297704.
4. ^ Zielinski, Raymond E. (1998). "Calmodulin and Calmodulin-Binding Proteins in Plants". Annual Review of Plant Physiology and Plant Molecular Biology. 49 (1): 697–725\. doi:10.1146/annurev.arplant.49.1.697. ISSN 1040-2519. PMID 15012251.
5. ^ Skene, J.H.Pate (1990). "GAP-43 as a 'calmodulin sponge' and some implications for calcium signalling in axon terminals". Neuroscience Research Supplements. 13: S112 – S125. doi:10.1016/0921-8696(90)90040-a. ISSN 0921-8696. PMID 1979675.

## External links

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* Calmodulin-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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