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 . 429–437 . September 1991 . 1796905 . 10.1002/bies.950130902 . 7958541 .
• Balvay L, Fiszman MY . [Analysis of the diversity of tropomyosin isoforms] . Comptes Rendus des Séances de la Société de Biologie et de ses Filiales . 188 . 5–6 . 527–540 . 1995 . 7780795 .
• Gunning P, Weinberger R, Jeffrey P . Actin and tropomyosin isoforms in morphogenesis . Anatomy and Embryology . 195 . 4 . 311–315 . April 1997 . 9108196 . 10.1007/s004290050050 . 9692297 .
• Perry SV . Vertebrate tropomyosin: distribution, properties and function . Journal of Muscle Research and Cell Motility . 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? . Journal of Muscle Research and Cell Motility . 24 . 8 . 593–596 . 2004 . 14870975 . 10.1023/B:JURE.0000009811.95652.68 . 32621707 .
• Jääskeläinen P, Miettinen R, Kärkkäinen P, Toivonen L, Laakso M, Kuusisto J . Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes . Annals of Medicine . 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 . Proceedings of the National Academy of Sciences of the United States of America . 75 . 8 . 3588–3592 . August 1978 . 278975 . 392830 . 10.1073/pnas.75.8.3588 . free . 1978PNAS...75.3588M .
• Höner B, Shoeman RL, Traub P . Degradation of cytoskeletal proteins by the human immunodeficiency virus type 1 protease . Cell Biology International Reports . 16 . 7 . 603–612 . July 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 . Proceedings of the National Academy of Sciences of the United States of America . 89 . 13 . 5789–5793 . July 1992 . 1631061 . 402103 . 10.1073/pnas.89.13.5789 . free . 1992PNAS...89.5789C .
• Shoeman RL, Kesselmier C, Mothes E, Höner B, Traub P . Non-viral cellular substrates for human immunodeficiency virus type 1 protease . FEBS Letters . 278 . 2 . 199–203 . January 1991 . 1991513 . 10.1016/0014-5793(91)80116-K . free . 1991FEBSL.278..199S .
• Cho YJ, Liu J, Hitchcock-DeGregori SE . The amino terminus of muscle tropomyosin is a major determinant for function . The Journal of Biological Chemistry . 265 . 1 . 538–545 . January 1990 . 2136742 . 10.1016/S0021-9258(19)40264-0 . free .
• Colote S, Widada JS, Ferraz C, Bonhomme F, Marti J, Liautard JP . Evolution of tropomyosin functional domains: differential splicing and genomic constraints . Journal of Molecular Evolution . 27 . 3 . 228–235 . 1988 . 3138425 . 10.1007/BF02100079 . 24795087 . 1988JMolE..27..228C .
• Lin CS, Leavitt J . Cloning and characterization of a cDNA encoding transformation-sensitive tropomyosin isoform 3 from tumorigenic human fibroblasts . Molecular and Cellular Biology . 8 . 1 . 160–168 . January 1988 . 3336357 . 363096 . 10.1128/mcb.8.1.160 .
• MacLeod AR, Gooding C . Human hTM alpha gene: expression in muscle and nonmuscle tissue . Molecular and Cellular Biology . 8 . 1 . 433–440 . January 1988 . 3336363 . 363144 . 10.1128/mcb.8.1.433 .
• 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 . Biochemical and Biophysical Research Communications . 142 . 3 . 813–818 . February 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 . The Journal of Biological Chemistry . 262 . 21 . 9971–9978 . July 1987 . 3611073 . 10.1016/S0021-9258(18)61061-0 . free .
• Brown HR, Schachat FH . Renaturation of skeletal muscle tropomyosin: implications for in vivo assembly . Proceedings of the National Academy of Sciences of the United States of America . 82 . 8 . 2359–2363 . April 1985 . 3857586 . 397557 . 10.1073/pnas.82.8.2359 . free . 1985PNAS...82.2359B .
• Tanokura M, Ohtsuki I . Interactions among chymotryptic troponin T subfragments, tropomyosin, troponin I and troponin C . Journal of Biochemistry . 95 . 5 . 1417–1421 . May 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 . The Journal of Biological Chemistry . 258 . 4 . 2534–2542 . February 1983 . 6822572 . 10.1016/S0021-9258(18)32959-4 . 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, Børglum AD . Refined localization of the human alpha-tropomyosin gene (TPM1) by genetic mapping . Cytogenetics and Cell Genetics . 84 . 1–2 . 35–36 . 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 . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
3. Brown JH, Kim KH, Jun G, Greenfield NJ, Dominguez R, Volkmann N, Hitchcock-DeGregori SE, Cohen C . Deciphering the design of the tropomyosin molecule . Proceedings of the National Academy of Sciences of the United States of America . 98 . 15 . 8496–8501 . July 2001 . 11438684 . 37464 . 10.1073/pnas.131219198 . free . 2001PNAS...98.8496B .
4. Yin Z, Ren J, Guo W . 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 . January 2015 . 25446994 . 4268308 . 10.1016/j.bbadis.2014.11.003 .
5. McKillop DF, Geeves MA . Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament . Biophysical Journal . 65 . 2 . 693–701 . August 1993 . 8218897 . 1225772 . 10.1016/S0006-3495(93)81110-X . 1993BpJ....65..693M .
6. Tardiff JC . Thin filament mutations: developing an integrative approach to a complex disorder . Circulation Research . 108 . 6 . 765–782 . March 2011 . 21415410 . 3075069 . 10.1161/CIRCRESAHA.110.224170 .
7. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–1053 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .