Biology:TPM1

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

Generic protein structure example

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. 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. 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. 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.

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, 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.

Further reading

• "The molecular basis for tropomyosin isoform diversity". BioEssays 13 (9): 429–437. September 1991. doi:10.1002/bies.950130902. PMID 1796905. 
• "[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. PMID 7780795. 
• "Actin and tropomyosin isoforms in morphogenesis". Anatomy and Embryology 195 (4): 311–315. April 1997. doi:10.1007/s004290050050. PMID 9108196. 
• "Vertebrate tropomyosin: distribution, properties and function". Journal of Muscle Research and Cell Motility 22 (1): 5–49. 2002. doi:10.1023/A:1010303732441. PMID 11563548. 
• "What is the role of tropomyosin in the regulation of muscle contraction?". Journal of Muscle Research and Cell Motility 24 (8): 593–596. 2004. doi:10.1023/B:JURE.0000009811.95652.68. PMID 14870975. 
• "Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes". Annals of Medicine 36 (1): 23–32. 2004. doi:10.1080/07853890310017161. PMID 15000344. 
• "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. doi:10.1073/pnas.75.8.3588. PMID 278975. Bibcode: 1978PNAS...75.3588M. 
• "Degradation of cytoskeletal proteins by the human immunodeficiency virus type 1 protease". Cell Biology International Reports 16 (7): 603–612. July 1992. doi:10.1016/S0309-1651(06)80002-0. PMID 1516138. 
• "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. doi:10.1073/pnas.89.13.5789. PMID 1631061. Bibcode: 1992PNAS...89.5789C. 
• "Non-viral cellular substrates for human immunodeficiency virus type 1 protease". FEBS Letters 278 (2): 199–203. January 1991. doi:10.1016/0014-5793(91)80116-K. PMID 1991513. Bibcode: 1991FEBSL.278..199S. 
• "The amino terminus of muscle tropomyosin is a major determinant for function". The Journal of Biological Chemistry 265 (1): 538–545. January 1990. doi:10.1016/S0021-9258(19)40264-0. PMID 2136742. 
• "Evolution of tropomyosin functional domains: differential splicing and genomic constraints". Journal of Molecular Evolution 27 (3): 228–235. 1988. doi:10.1007/BF02100079. PMID 3138425. Bibcode: 1988JMolE..27..228C. 
• "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. doi:10.1128/mcb.8.1.160. PMID 3336357. 
• "Human hTM alpha gene: expression in muscle and nonmuscle tissue". Molecular and Cellular Biology 8 (1): 433–440. January 1988. doi:10.1128/mcb.8.1.433. PMID 3336363. 
• "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. doi:10.1016/0006-291X(87)91486-0. PMID 3548719. Bibcode: 1987BBRC..142..813M. 
• "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. doi:10.1016/S0021-9258(18)61061-0. PMID 3611073. 
• "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. doi:10.1073/pnas.82.8.2359. PMID 3857586. Bibcode: 1985PNAS...82.2359B. 
• "Interactions among chymotryptic troponin T subfragments, tropomyosin, troponin I and troponin C". Journal of Biochemistry 95 (5): 1417–1421. May 1984. doi:10.1093/oxfordjournals.jbchem.a134749. PMID 6746613. 
• "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. doi:10.1016/S0021-9258(18)32959-4. PMID 6822572. 

External links

• Mass spectrometry characterization of human TPM1 at COPaKB
• GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview
• Overview of all the structural information available in the PDB for UniProt: P09493 (Tropomyosin alpha-1 chain) at the PDBe-KB.