Biology:Calponin 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[3][4] calponin 2,[5] calponin 3,[6] 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[7] with a higher content in phasic smooth muscle of the digestive tract.[8]

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.[9] However, the CH domain in calponin is not the binding site for actin nor does it regulate the modes of calponin-F-actin binding.[10] 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.[11]

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.[12][13][14] 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.[15][16][17]

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.[18][19] The C-terminal tail regulates the interaction with F-actin by altering the function of the second actin-bing site of calponin.[20]

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][21][22] In this regulation, binding of Ca2+-calmodulin and PKC phosphorylation dissociate calponin 1 from the actin filament and facilitate smooth muscle contraction.[23]

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.[24][25] Matrix metalloproteinase-2 proteolysis of calponin 1 resulted in vascular hypocontractility to phenylephrine.[26] Vas deferens smooth muscle from calponin 1 knockout mice showed faster maximum shortening velocity.[27] Calponin 1 knockout mice exhibited blunted MAP response to phenylephrine administration.[28]

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.[23] Direct association was found between calponin 1 and PKCα[29] and PKCε.[11] Calmodulin-dependent kinase II and Rho-kinase are also found to phosphorylate calponin at Ser175 and Thr184 in vitro.[30][31] 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[32][33]

Unphosphorylated calponin binds to actin and inhibits actomyosin MgATPase. Ser175 phosphorylation alters the molecular conformation of calponin and dissociates calponin from F-actin.[34] The consequence is to release the inhibition of actomyosin MgATPase and increase the production of force.[14][35][36]

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.[37][38] Based on the observation that PKC phosphorylation of calponin 1 weakens the binding affinity for the actin filaments,[34] the phosphorylated calponin may not be stable in the actin cytoskeleton thus be degraded in the cell.

Notes

References

  1. ↑ "Entrez Gene: calponin 1, basic, smooth muscle". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1264. 
  2. ↑ 2.0 2.1 "A novel troponin T-like protein (calponin) in vascular smooth muscle: interaction with tropomyosin paracrystals". Journal of Hypertension Supplement 6 (4): S40–3. December 1988. doi:10.1097/00004872-198812040-00008. PMID 3241227. 
  3. ↑ 3.0 3.1 "Complete nucleotide sequence, structural organization, and an alternatively spliced exon of mouse h1-calponin gene". Biochemical and Biophysical Research Communications 218 (1): 292–7. January 1996. doi:10.1006/bbrc.1996.0051. PMID 8573148. 
  4. ↑ "Mammalian calponin. Identification and expression of genetic variants". FEBS Letters 330 (1): 13–8. September 1993. doi:10.1016/0014-5793(93)80909-e. PMID 8370452. 
  5. ↑ "Molecular cloning and characterization of human non-smooth muscle calponin". Journal of Biochemistry 120 (2): 415–24. August 1996. doi:10.1093/oxfordjournals.jbchem.a021428. PMID 8889829. 
  6. ↑ "Cloning and expression of a novel acidic calponin isoform from rat aortic vascular smooth muscle". The Journal of Biological Chemistry 269 (14): 10683–90. April 1994. doi:10.1016/S0021-9258(17)34113-3. PMID 8144658. 
  7. ↑ "Developmentally regulated expression of calponin isoforms and the effect of h2-calponin on cell proliferation". American Journal of Physiology. Cell Physiology 284 (1): C156–67. January 2003. doi:10.1152/ajpcell.00233.2002. PMID 12388067. 
  8. ↑ "Expression and epitopic conservation of calponin in different smooth muscles and during development". Biochemistry and Cell Biology 74 (2): 187–96. 1996. doi:10.1139/o96-019. PMID 9213427. 
  9. ↑ "Functional plasticity of CH domains". FEBS Letters 513 (1): 98–106. February 2002. doi:10.1016/s0014-5793(01)03240-9. PMID 11911887. 
  10. ↑ "The CH-domain of calponin does not determine the modes of calponin binding to F-actin". Journal of Molecular Biology 359 (2): 478–85. June 2006. doi:10.1016/j.jmb.2006.03.044. PMID 16626733. 
  11. ↑ 11.0 11.1 "Extracellular regulated kinase (ERK) interaction with actin and the calponin homology (CH) domain of actin-binding proteins". The Biochemical Journal 344 (1): 117–23. November 1999. doi:10.1042/0264-6021:3440117. PMID 10548541. 
  12. ↑ "Effect of calponin on actin-activated myosin ATPase activity". Journal of Biochemistry 108 (5): 835–8. November 1990. doi:10.1093/oxfordjournals.jbchem.a123289. PMID 2150518. 
  13. ↑ "Mapping of the functional domains in the amino-terminal region of calponin". The Journal of Biological Chemistry 267 (22): 15943–51. August 1992. doi:10.1016/S0021-9258(19)49625-7. PMID 1639822. 
  14. ↑ 14.0 14.1 "Calponin: thin filament-linked regulation of smooth muscle contraction". Cellular Signalling 5 (6): 677–86. November 1993. doi:10.1016/0898-6568(93)90029-l. PMID 8130072. 
  15. ↑ "Isoform diversity, regulation, and functional adaptation of troponin and calponin". Critical Reviews in Eukaryotic Gene Expression 18 (2): 93–124. 2008. doi:10.1615/critreveukargeneexpr.v18.i2.10. PMID 18304026. 
  16. ↑ "Calponin in non-muscle cells". Cell Biochemistry and Biophysics 52 (3): 139–48. 2008. doi:10.1007/s12013-008-9031-6. PMID 18946636. 
  17. ↑ "Calponin: A mechanical tension-modulated regulator of cytoskeleton and cell motility.". Current Topics in Biochemical Research 16: 1–15. 2015. 
  18. ↑ "Fluorescence studies of the carboxyl-terminal domain of smooth muscle calponin effects of F-actin and salts". European Journal of Biochemistry 262 (2): 335–41. June 1999. doi:10.1046/j.1432-1327.1999.00390.x. PMID 10336616. 
  19. ↑ "Live dynamics of GFP-calponin: isoform-specific modulation of the actin cytoskeleton and autoregulation by C-terminal sequences". Journal of Cell Science 113 (21): 3725–36. November 2000. doi:10.1242/jcs.113.21.3725. PMID 11034901. 
  20. ↑ "The molecular basis for the autoregulation of calponin by isoform-specific C-terminal tail sequences". Journal of Cell Science 115 (Pt 10): 2021–9. May 2002. doi:10.1242/jcs.115.10.2021. PMID 11973344. 
  21. ↑ "Isolation and characterization of a 34,000-dalton calmodulin- and F-actin-binding protein from chicken gizzard smooth muscle". Biochemical and Biophysical Research Communications 141 (1): 20–6. November 1986. doi:10.1016/s0006-291x(86)80328-x. PMID 3606745. 
  22. ↑ "The biochemical basis of the regulation of smooth-muscle contraction". Trends in Biochemical Sciences 19 (9): 362–8. September 1994. doi:10.1016/0968-0004(94)90112-0. PMID 7985229. 
  23. ↑ 23.0 23.1 "Modulation of smooth muscle calponin by protein kinase C and calmodulin". Biochemical and Biophysical Research Communications 171 (3): 933–7. September 1990. doi:10.1016/0006-291x(90)90773-g. PMID 2222454. 
  24. ↑ "h1- and h2-calponins are not essential for norepinephrine- or sodium fluoride-induced contraction of rat aortic smooth muscle". Journal of Muscle Research and Cell Motility 19 (6): 695–703. August 1998. doi:10.1023/a:1005389300151. PMID 9742453. 
  25. ↑ "The maximal velocity of vascular smooth muscle shortening is independent of the expression of calponin". Journal of Muscle Research and Cell Motility 21 (4): 367–73. May 2000. doi:10.1023/a:1005680614296. PMID 11032347. 
  26. ↑ "Matrix metalloproteinase-2 proteolysis of calponin-1 contributes to vascular hypocontractility in endotoxemic rats". Arteriosclerosis, Thrombosis, and Vascular Biology 32 (3): 662–8. March 2012. doi:10.1161/ATVBAHA.111.242685. PMID 22199370. 
  27. ↑ "Regulation of shortening velocity by calponin in intact contracting smooth muscles". Biochemical and Biophysical Research Communications 279 (1): 150–7. December 2000. doi:10.1006/bbrc.2000.3909. PMID 11112431. 
  28. ↑ "Enhanced baroreflex sensitivity in free-moving calponin knockout mice". American Journal of Physiology. Heart and Circulatory Physiology 284 (3): H939–46. March 2003. doi:10.1152/ajpheart.00610.2002. PMID 12433658. 
  29. ↑ "Direct association of calponin with specific domains of PKC-alpha". American Journal of Physiology. Gastrointestinal and Liver Physiology 295 (6): G1246–54. December 2008. doi:10.1152/ajpgi.90461.2008. PMID 18948438. 
  30. ↑ "The Ayerst Award Lecture 1990. Calcium-dependent mechanisms of regulation of smooth muscle contraction". Biochemistry and Cell Biology 69 (12): 771–800. December 1991. doi:10.1139/o91-119. PMID 1818584. 
  31. ↑ "Identification of calponin as a novel substrate of Rho-kinase". Biochemical and Biophysical Research Communications 273 (1): 110–6. June 2000. doi:10.1006/bbrc.2000.2901. PMID 10873572. 
  32. ↑ "Dephosphorylation of calponin by type 2B protein phosphatase". Biochemistry 34 (28): 9151–8. July 1995. doi:10.1021/bi00028a026. PMID 7619814. 
  33. ↑ "Calponin phosphatase from smooth muscle: a possible role of type 1 protein phosphatase in smooth muscle relaxation". Biochemical and Biophysical Research Communications 193 (3): 827–33. June 1993. doi:10.1006/bbrc.1993.1700. PMID 8391807. 
  34. ↑ 34.0 34.1 "A role for serine-175 in modulating the molecular conformation of calponin". The Biochemical Journal 350 (2): 579–88. September 2000. doi:10.1042/0264-6021:3500579. PMID 10947974. 
  35. ↑ "Structure-function relations of smooth muscle calponin. The critical role of serine 175". The Journal of Biological Chemistry 271 (15): 8605–11. April 1996. doi:10.1074/jbc.271.15.8605. PMID 8621490. 
  36. ↑ "Caldesmon and calponin phosphorylation in regulation of smooth muscle contraction". Canadian Journal of Physiology and Pharmacology 72 (11): 1410–4. November 1994. doi:10.1139/y94-203. PMID 7767886. 
  37. ↑ "Calponin phosphorylation does not accompany contraction of various smooth muscles". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1179 (2): 229–33. November 1993. doi:10.1016/0167-4889(93)90146-g. PMID 8218366. 
  38. ↑ "Calponin and SM 22 isoforms in avian and mammalian smooth muscle. Absence of phosphorylation in vivo". European Journal of Biochemistry 205 (3): 1067–75. May 1992. doi:10.1111/j.1432-1033.1992.tb16875.x. PMID 1576991. 



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