TPM1 explained

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene.^[1] This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

Structure

Tm is a 32.7 kDa protein composed of 284 amino acids.^[2] Tm is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle.^[3] It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. Human striated muscles express protein from the TPM1 (α-Tm), TPM2 (β-Tm) and TPM3 (γ-Tm) genes, with α-Tm being the predominant isoform in striated muscle. In human cardiac muscle the ratio of α-Tm to β-Tm is roughly 5:1.^[4]

Function

Tm functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. Tm molecules are arranged head-to-tail along the actin thin filament, and are a key component in cooperative activation of muscle. A three state model has been proposed by McKillop and Geeves,^[5] which describes the positions of Tm during a cardiac cycle. The blocked (B) state occurs in diastole when intracellular calcium is low and Tm blocks the myosin binding site on actin. The closed (C) state is when Tm is positioned on the inner groove of actin; in this state myosin is in a "cocked" position where heads are weakly bound and not generating force. The myosin binding (M) state is when Tm is further displaced from actin by myosin crossbridges that are strongly-bound and actively generating force. In addition to actin, Tm binds troponin T (TnT). TnT tethers the region of head-to-tail overlap of subsequent Tm molecules to actin.

Clinical Significance

Mutations in TPM1 have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy (LVNC). HCM mutations tend to cluster around the N-terminal region and a primary actin binding region known as period 5.^[6]

Further reading

• Lees-Miller JP, Helfman DM . The molecular basis for tropomyosin isoform diversity. . BioEssays . 13 . 9 . 429–37 . 1992 . 1796905 . 10.1002/bies.950130902 . 7958541 .
• Balvay L, Fiszman MY . [Analysis of the diversity of tropomyosin isoforms] . C. R. Séances Soc. Biol. Fil. . 188 . 5–6 . 527–40 . 1995 . 7780795 .
• Gunning P, Weinberger R, Jeffrey P . Actin and tropomyosin isoforms in morphogenesis. . Anat. Embryol. . 195 . 4 . 311–5 . 1997 . 9108196 . 10.1007/s004290050050 . 9692297 .
• Perry SV . Vertebrate tropomyosin: distribution, properties and function. . J. Muscle Res. Cell. Motil. . 22 . 1 . 5–49 . 2002 . 11563548 . 10.1023/A:1010303732441 . 12346005 .
• Perry SV . What is the role of tropomyosin in the regulation of muscle contraction? . J. Muscle Res. Cell. Motil. . 24 . 8 . 593–6 . 2004 . 14870975 . 10.1023/B:JURE.0000009811.95652.68 . 32621707 .
• Jääskeläinen P, Miettinen R, Kärkkäinen P, etal . Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes. . Ann. Med. . 36 . 1 . 23–32 . 2004 . 15000344 . 10.1080/07853890310017161 . 29985750 . free .
• Mak A, Smillie LB, Bárány M . Specific phosphorylation at serine-283 of alpha tropomyosin from frog skeletal and rabbit skeletal and cardiac muscle. . Proc. Natl. Acad. Sci. U.S.A. . 75 . 8 . 3588–92 . 1978 . 278975 . 10.1073/pnas.75.8.3588 . 392830 . 1978PNAS...75.3588M . free .
• Höner B, Shoeman RL, Traub P . Degradation of cytoskeletal proteins by the human immunodeficiency virus type 1 protease. . Cell Biol. Int. Rep. . 16 . 7 . 603–12 . 1992 . 1516138 . 10.1016/S0309-1651(06)80002-0 .
• Chevray PM, Nathans D . Protein interaction cloning in yeast: identification of mammalian proteins that react with the leucine zipper of Jun. . Proc. Natl. Acad. Sci. U.S.A. . 89 . 13 . 5789–93 . 1992 . 1631061 . 10.1073/pnas.89.13.5789 . 402103 . 1992PNAS...89.5789C . free .
• Shoeman RL, Kesselmier C, Mothes E, etal . Non-viral cellular substrates for human immunodeficiency virus type 1 protease. . FEBS Lett. . 278 . 2 . 199–203 . 1991 . 1991513 . 10.1016/0014-5793(91)80116-K . free .
• Cho YJ, Liu J, Hitchcock-DeGregori SE . The amino terminus of muscle tropomyosin is a major determinant for function. . J. Biol. Chem. . 265 . 1 . 538–45 . 1990 . 10.1016/S0021-9258(19)40264-0 . 2136742 . free .
• Colote S, Widada JS, Ferraz C, etal . Evolution of tropomyosin functional domains: differential splicing and genomic constraints. . J. Mol. Evol. . 27 . 3 . 228–35 . 1988 . 3138425 . 10.1007/BF02100079 . 1988JMolE..27..228C . 24795087 .
• Lin CS, Leavitt J . Cloning and characterization of a cDNA encoding transformation-sensitive tropomyosin isoform 3 from tumorigenic human fibroblasts. . Mol. Cell. Biol. . 8 . 1 . 160–8 . 1988 . 3336357 . 10.1128/mcb.8.1.160. 363096 .
• MacLeod AR, Gooding C . Human hTM alpha gene: expression in muscle and nonmuscle tissue. . Mol. Cell. Biol. . 8 . 1 . 433–40 . 1988 . 3336363 . 10.1128/mcb.8.1.433. 363144 .
• Mische SM, Manjula BN, Fischetti VA . Relation of streptococcal M protein with human and rabbit tropomyosin: the complete amino acid sequence of human cardiac alpha tropomyosin, a highly conserved contractile protein. . Biochem. Biophys. Res. Commun. . 142 . 3 . 813–8 . 1987 . 3548719 . 10.1016/0006-291X(87)91486-0 .
• Heeley DH, Golosinska K, Smillie LB . The effects of troponin T fragments T1 and T2 on the binding of nonpolymerizable tropomyosin to F-actin in the presence and absence of troponin I and troponin C. . J. Biol. Chem. . 262 . 21 . 9971–8 . 1987 . 10.1016/S0021-9258(18)61061-0 . 3611073 . free .
• Brown HR, Schachat FH . Renaturation of skeletal muscle tropomyosin: implications for in vivo assembly. . Proc. Natl. Acad. Sci. U.S.A. . 82 . 8 . 2359–63 . 1985 . 3857586 . 10.1073/pnas.82.8.2359 . 397557 . 1985PNAS...82.2359B . free .
• Tanokura M, Ohtsuki I . Interactions among chymotryptic troponin T subfragments, tropomyosin, troponin I and troponin C. . J. Biochem. . 95 . 5 . 1417–21 . 1984 . 6746613 . 10.1093/oxfordjournals.jbchem.a134749.
• Pearlstone JR, Smillie LB . Effects of troponin-I plus-C on the binding of troponin-T and its fragments to alpha-tropomyosin. Ca2+ sensitivity and cooperativity. . J. Biol. Chem. . 258 . 4 . 2534–42 . 1983 . 10.1016/S0021-9258(18)32959-4 . 6822572 . free .

External links

• Mass spectrometry characterization of human TPM1 at COPaKB ^[7]
• GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview

Notes and References

1. Mogensen J, Kruse TA, Borglum AD . Refined localization of the human alpha-tropomyosin gene (TPM1) by genetic mapping . Cytogenet Cell Genet . 84 . 1–2 . 35–6 . Jun 1999 . 10343096 . 10.1159/000015207 . 84901339 .
2. Web site: Protein Information . 25 May 2023 . https://web.archive.org/web/20150924025508/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P09493 . September 24, 2015 . en . unfit.
3. 11438684. 37464. 2001. Brown. J. H.. Deciphering the design of the tropomyosin molecule. Proceedings of the National Academy of Sciences. 98. 15. 8496–501. Kim. K. H.. Jun. G. Greenfield. N. J.. Dominguez. R. Volkmann. N. Hitchcock-Degregori. S. E.. Cohen. C. 10.1073/pnas.131219198. 2001PNAS...98.8496B. free.
4. 25446994. 4268308. 2015. Yin. Z. Sarcomeric protein isoform transitions in cardiac muscle: A journey to heart failure. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852. 1. 47–52. Ren. J. Guo. W. 10.1016/j.bbadis.2014.11.003.
5. 8218897. 1225772. 1993. McKillop. D. F.. Regulation of the interaction between actin and myosin subfragment 1: Evidence for three states of the thin filament. Biophysical Journal. 65. 2. 693–701. Geeves. M. A.. 10.1016/S0006-3495(93)81110-X. 1993BpJ....65..693M.
6. 21415410. 3075069. 2011. Tardiff. J. C.. Thin filament mutations: Developing an integrative approach to a complex disorder. Circulation Research. 108. 6. 765–82. 10.1161/CIRCRESAHA.110.224170.
7. 23965338. 4076475. 2013. Zong. N. C.. Integration of cardiac proteome biology and medicine by a specialized knowledgebase. Circulation Research. 113. 9. 1043–53. Li. H. Li. H. Lam. M. P.. Jimenez. R. C.. Kim. C. S.. Deng. N. Kim. A. K.. Choi. J. H.. Zelaya. I. Liem. D. Meyer. D. Odeberg. J. Fang. C. Lu. H. J.. Xu. T. Weiss. J. Duan. H. Uhlen. M. Yates Jr. 3rd. Apweiler. R. Ge. J. Hermjakob. H. Ping. P. 10.1161/CIRCRESAHA.113.301151.