Calponin 1

calponin 1, basic, smooth muscle
Identifiers
Symbol CNN1
External IDs OMIM: 600806 HomoloGene: 995 GeneCards: CNN1 Gene
Orthologs
Species Human Mouse
Entrez 1264 12797
Ensembl ENSG00000130176 ENSMUSG00000001349
UniProt P51911 Q08091
RefSeq (mRNA) XM_011527690.1 XM_011242388.1
RefSeq (protein) XP_011525992.1 XP_011240690.1
Location (UCSC) Chr 19:
11.54 – 11.55 Mb		 Chr 9:
22.1 – 22.11 Mb
PubMed search

Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.[1]

The CNN1 gene is located at 19p13.2-p13.1 in the human chromosomal genome and contains 7 exons, encoding the protein calponin 1, an actin filament-associated regulatory protein.[2] Human calponin 1 is a 33.2-KDa protein consists of 297 amino acids with an isoelectric point of 9.1,[3] thus calponin 1 is also known as basic calponin.

Evolution

Figure 1: Evolutionary lineage of vertebrate CNN1.

Three homologous genes, Cnn1, Cnn2 and Cnn3, have evolved in vertebrates, encoding three isoforms of calponin: calponin 1,[4][5] calponin 2,[6] calponin 3,[7] respectively. Protein sequence alignment shows that calponin 1 is highly conserved in mammals but more diverged among lower vertebrates.

Smooth muscle-specific expression

The expression of CNN1 is specific to differentiated mature smooth muscle cells, suggesting a role in contractile functions. Calponin 1 is up-regulated in smooth muscle tissues during postnatal development[8] with a higher content in phasic smooth muscle of the digestive tract.[9]

Structure-function relationship

Figure 2. Structural and functional domains of calponin. The linear structural map summarized primarily from studies of chicken calponin 1 illustrates the structural and functional domains of calponin. The CH domain, two actin-binding sites, three repeating sequence motifs, and the C-terminal variable region are outlined. The CH domain overlaps with the ERK signaling binding region. Amino acid sequences of the two actin-binding sites in the three isoforms and the three repeating motifs of calponin 1 are shown in the insets. The regulatory phosphorylation sites Ser175 and Thr184 are located in the second actin-binding site that overlaps with the first repeating motif. Potentially phosphorylatable serine residues corresponding to Ser175 are conserved in repeats 2 and 3, while a Thr184 equivalent is conserved in repeat 2. Different from calponin 1 and calponin 3, calponin 2 has a potentially phosphorylatable additional serine at position 177.

The majority of structure-function relationship studies of calponin were with experiments using chicken calponin 1. Primary structure of calponin consists of a conserved N-terminal calponin homology (CH) domain, a conserved middle region containing two actin-binding sites, and a C-terminal variable region that contributes to the differences among there isoforms.

The CH domain

The CH domain was found in a number of actin-binding proteins (such as α-actinin, spectrin, and filamin) to form the actin-binding region or serve as a regulatory structure.[10] However, the CH domain in calponin is not the binding site for actin nor does it regulate the modes of calponin-F-actin binding.[11] Nonetheless, CH domain in calponin was found to bind to extra-cellular regulated kinase (ERK) for calponin to play a possible role as an adaptor protein in the ERK signaling cascades.[12]

Actin-binding sites

Calponin binds actin to promote and sustain polymerization. The binding of calponin to F-actin inhibits the MgATPase activity of smooth muscle myosin.[13][14][15][16] Calponin binds F-actin through two sites at residues 144-162 and 171-188 in chicken calponin 1. The two actin-binding sites are conserved in the three calponin isoforms.

There are three repeating sequence motifs in calponin next to the C-terminal region. This repeating structure is conserved in all three isoforms and across species. Outlined in Fig. 2, the first repeating motif overlaps with the second actin-binding site and contains protein kinase C (PKC) phosphorylation sites Ser175 and Thr184 that are not present in the first actin-binding site. This feature is consistent with the hypothesis that the second actin-binding site plays a regulatory role in the binding of calponin to the actin filament. Similar sequences as well as potential phosphorylation sites are present in repeats 2 and 3 whereas their function is unknown.

C-terminal variable region

The C-terminal segment of calponin has diverged significantly among the three isoforms. The variable lengths and amino acid sequences of the C-terminal segment produce the size and charge differences among the calponin isoforms. The corresponding charge features rendered calponin 1, 2 and 3 the names of basic, neutral and acidic calponins.[17][18][19]

The C-terminal segment of calponin has an effect on weakening the binding of calponin to F-actin. Deletion of the C-terminal tail strongly enhanced the actin-binding and bundling activities of all three isoforms of calponin.[20][21] The C-terminal tail regulates the interaction with F-actin by altering the function of the second actin-bing site of calponin.[22]

Regulation of smooth muscle contractility

Numerous in vitro experimental data indicate that calponin 1 functions as an inhibitory regulator of smooth muscle contractility through inhibiting actomyosin interactions.[2][23][24] In this regulation, binding of Ca2+-calmodulin and PKC phosphorylation dissociate calponin 1 from the actin filament and facilitate smooth muscle contraction.[25]

In vivo data also support the role of calponin 1 as regulator of smooth muscle contractility. While aortic smooth muscle of adult Wistar Kyoto rats, which naturally lacks calponin 1, is fully contractile, it has a decreased sensitivity to norepinephrine activation.[26][27] Matrix metalloproteinase-2 proteolysis of calponin 1 resulted in vascular hypocontractility to phenylephrine.[28] Vas deferens smooth muscle from calponin 1 knockout mice showed faster maximum shortening velocity.[29] Calponin 1 knockout mice exhibited blunted MAP response to phenylephrine administration.[30]

Phosphorylation regulation

There is a large collection of in vitro evidences demonstrating the phosphorylation regulation of calponin. The primary phosphorylation sites are Ser175 and Thr184 in the second actin-binding site (Fig. 2). Experimental data showed that Ser175 and Thr184 in calponin 1 are phosphorylated by PKC in vitro.[25] Direct association was found between calponin 1 and PKCα [31] and PKCε.[12] Calmodulin-dependent kinase II and Rho-kinase are also found to phosphorylate calponin at Ser175 and Thr184 in vitro.[32][33] Of these two residues, the main site of regulatory phosphorylation by calmodulin-dependent kinase II and Rho-kinase is Ser175. Dephosphorylation of calponin is catalyzed by type 2B protein phosphatase [34][35]

Unphosphorylated calponin binds to actin and inhibits actomyosin MgATPase. Ser175 phosphorylation alters the molecular conformation of calponin and dissociates calponin from F-actin.[36] The consequence is to release the inhibition of actomyosin MgATPase and increase the production of force.[16][37][38]

Despite the overwhelming evidence for the phosphorylation regulation of calponin obtained from in vitro studies, phosphorylated calponin is not readily detectable in vivo or in living cells under physiological conditions.[39][40] Based on the observation that PKC phosphorylation of calponin 1 weakens the binding affinity for the actin filaments,[36] the phosphorylated calponin may not be stable in the actin cytoskeleton thus be degraded in the cell.

References

  1. ↑ "Entrez Gene: calponin 1, basic, smooth muscle".
  2. 1 2 Takahashi, K., Abe, M., Hiwada, K. and Kokubu, T., 1988. A novel troponin T-like protein (calponin) in vascular smooth muscle: interaction with tropomyosin paracrystals. J Hypertens Suppl 6, S40-3.
  3. ↑ Gao, J., Hwang, J.M. and Jin, J.P., 1996. Complete nucleotide sequence, structural organization, and an alternatively spliced exon of mouse h1-calponin gene. Biochem Biophys Res Commun 218, 292-7.
  4. ↑ Gao, J., Hwang, J.M. and Jin, J.P., 1996. Complete nucleotide sequence, structural organization, and an alternatively spliced exon of mouse h1-calponin gene. Biochem Biophys Res Commun 218, 292-7.
  5. ↑ Strasser, P., Gimona, M., Moessler, H., Herzog, M. and Small, J.V., 1993. Mammalian calponin. Identification and expression of genetic variants. FEBS Lett 330, 13-8.
  6. ↑ Masuda, H., Tanaka, K., Takagi, M., Ohgami, K., Sakamaki, T., Shibata, N. and Takahashi, K., 1996. Molecular cloning and characterization of human non-smooth muscle calponin. J Biochem 120, 415-24.
  7. ↑ Applegate, D., Feng, W., Green, R.S. and Taubman, M.B., 1994. Cloning and expression of a novel acidic calponin isoform from rat aortic vascular smooth muscle. J Biol Chem 269, 10683-90.
  8. ↑ Hossain, M.M., Hwang, D.Y., Huang, Q.Q., Sasaki, Y. and Jin, J.P., 2003. Developmentally regulated expression of calponin isoforms and the effect of h2-calponin on cell proliferation. Am J Physiol Cell Physiol 284, C156-67.
  9. ↑ Jin, J.P., Walsh, M.P., Resek, M.E. and McMartin, G.A., 1996. Expression and epitopic conservation of calponin in different smooth muscles and during development. Biochem Cell Biol 74, 187-96.
  10. ↑ Gimona, M., Djinovic-Carugo, K., Kranewitter, W.J. and Winder, S.J., 2002. Functional plasticity of CH domains. FEBS Lett 513, 98-106
  11. ↑ Galkin, V.E., Orlova, A., Fattoum, A., Walsh, M.P. and Egelman, E.H., 2006. The CH-domain of calponin does not determine the modes of calponin binding to F-actin. J Mol Biol 359, 478-85.
  12. 1 2 Leinweber, B.D., Leavis, P.C., Grabarek, Z., Wang, C.L. and Morgan, K.G., 1999. Extracellular regulated kinase (ERK) interaction with actin and the calponin homology (CH) domain of actin-binding proteins. Biochem J 344 Pt 1, 117-23.
  13. ↑ Winder, S.J. and Walsh, M.P., 1990. Smooth muscle calponin. Inhibition of actomyosin MgATPase and regulation by phosphorylation. J Biol Chem 265, 10148-55.
  14. ↑ Mezgueldi, M., Fattoum, A., Derancourt, J. and Kassab, R., 1992. Mapping of the functional domains in the amino-terminal region of calponin. J Biol Chem 267, 15943-51.
  15. ↑ Abe, M., Takahashi, K. and Hiwada, K., 1990. Effect of calponin on actin-activated myosin ATPase activity. J Biochem 108, 835-8.
  16. 1 2 Winder, S.J. and Walsh, M.P., 1993. Calponin: thin filament-linked regulation of smooth muscle contraction. Cell Signal 5, 677-86.
  17. ↑ Jin, J.P., Zhang, Z. and Bautista, J.A., 2008. Isoform diversity, regulation, and functional adaptation of troponin and calponin. Crit Rev Eukaryot Gene Expr 18, 93-124.
  18. ↑ Wu, K.C. and Jin, J.P., 2008. Calponin in non-muscle cells. Cell Biochem Biophys 52, 139-48.
  19. ↑ Liu, R. and Jin, J.P., 2015. Calponin: A mechanical tension-modulated regulator of cytoskeleton and cell motility. Current Topics in Biochemical Research 16, 1-15.
  20. ↑ Bartegi, A., Roustan, C., Kassab, R. and Fattoum, A., 1999. Fluorescence studies of the carboxyl-terminal domain of smooth muscle calponin effects of F-actin and salts. Eur J Biochem 262, 335-41.
  21. ↑ Danninger, C. and Gimona, M., 2000. Live dynamics of GFP-calponin: isoform-specific modulation of the actin cytoskeleton and autoregulation by C-terminal sequences. J Cell Sci 113 Pt 21, 3725-36.
  22. ↑ Burgstaller, G., Kranewitter, W.J. and Gimona, M., 2002. The molecular basis for the autoregulation of calponin by isoform-specific C-terminal tail sequences. J Cell Sci 115, 2021-9.
  23. ↑ Takahashi, K., Hiwada, K. and Kokubu, T., 1986. Isolation and characterization of a 34,000-dalton calmodulin- and F-actin-binding protein from chicken gizzard smooth muscle. Biochem Biophys Res Commun 141, 20-6.
  24. ↑ Allen, B.G. and Walsh, M.P., 1994. The biochemical basis of the regulation of smooth-muscle contraction. Trends Biochem Sci 19, 362-8.
  25. 1 2 Naka, M., Kureishi, Y., Muroga, Y., Takahashi, K., Ito, M. and Tanaka, T., 1990. Modulation of smooth muscle calponin by protein kinase C and calmodulin. Biochem Biophys Res Commun 171, 933-7.
  26. ↑ Nigam, R., Triggle, C.R. and Jin, J.P., 1998. h1- and h2-calponins are not essential for norepinephrine- or sodium fluoride-induced contraction of rat aortic smooth muscle. J Muscle Res Cell Motil 19, 695-703.
  27. ↑ Facemire, C., Brozovich, F.V. and Jin, J.P., 2000. The maximal velocity of vascular smooth muscle shortening is independent of the expression of calponin. J Muscle Res Cell Motil 21, 367-73.
  28. ↑ Castro, M.M., Cena, J., Cho, W.J., Walsh, M.P. and Schulz, R., 2012. Matrix metalloproteinase-2 proteolysis of calponin-1 contributes to vascular hypocontractility in endotoxemic rats. Arterioscler Thromb Vasc Biol 32, 662-8.
  29. ↑ Takahashi, K., Yoshimoto, R., Fuchibe, K., Fujishige, A., Mitsui-Saito, M., Hori, M., Ozaki, H., Yamamura, H., Awata, N., Taniguchi, S., Katsuki, M., Tsuchiya, T. and Karaki, H., 2000. Regulation of shortening velocity by calponin in intact contracting smooth muscles. Biochem Biophys Res Commun 279, 150-7.
  30. ↑ Masuki, S., Takeoka, M., Taniguchi, S. and Nose, H., 2003. Enhanced baroreflex sensitivity in free-moving calponin knockout mice. Am J Physiol Heart Circ Physiol 284, H939-46.
  31. ↑ Somara, S. and Bitar, K.N., 2008. Direct association of calponin with specific domains of PKC-alpha. Am J Physiol Gastrointest Liver Physiol 295, G1246-54.
  32. ↑ Walsh, M.P., 1991. The Ayerst Award Lecture 1990. Calcium-dependent mechanisms of regulation of smooth muscle contraction. Biochem Cell Biol 69, 771-800.
  33. ↑ Kaneko, T., Amano, M., Maeda, A., Goto, H., Takahashi, K., Ito, M. and Kaibuchi, K., 2000. Identification of calponin as a novel substrate of Rho-kinase. Biochem Biophys Res Commun 273, 110-6.
  34. ↑ Fraser, E.D. and Walsh, M.P., 1995. Dephosphorylation of calponin by type 2B protein phosphatase. Biochemistry 34, 9151-8.
  35. ↑ Ichikawa, K., Ito, M., Okubo, S., Konishi, T., Nakano, T., Mino, T., Nakamura, F., Naka, M. and Tanaka, T., 1993. Calponin phosphatase from smooth muscle: a possible role of type 1 protein phosphatase in smooth muscle relaxation. Biochem Biophys Res Commun 193, 827-33.
  36. 1 2 Jin, J.P., Walsh, M.P., Sutherland, C. and Chen, W., 2000. A role for serine-175 in modulating the molecular conformation of calponin. Biochem J 350 Pt 2, 579-88.
  37. ↑ Tang, D.C., Kang, H.M., Jin, J.P., Fraser, E.D. and Walsh, M.P., 1996. Structure-function relations of smooth muscle calponin. The critical role of serine 175. J Biol Chem 271, 8605-11.
  38. ↑ Gerthoffer, W.T. and Pohl, J., 1994. Caldesmon and calponin phosphorylation in regulation of smooth muscle contraction. Can J Physiol Pharmacol 72, 1410-4.
  39. ↑ Barany, M. and Barany, K., 1993. Calponin phosphorylation does not accompany contraction of various smooth muscles. Biochim Biophys Acta 1179, 229-33.
  40. ↑ Gimona, M., Sparrow, M.P., Strasser, P., Herzog, M. and Small, J.V., 1992. Calponin and SM 22 isoforms in avian and mammalian smooth muscle. Absence of phosphorylation in vivo. Eur J Biochem 205, 1067-75.
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