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Pengguna:Hidayatsrf/Bak pasir

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Revisi sejak 19 Januari 2018 13.59 oleh Hidayatsrf (bicara | kontrib)

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Titin /ˈtaɪtɪn/, juga dikenal sebagai connectin, adalah suatu protein yang pada manusia, dikodekan oleh gen TTN.[1][2] Titin adalah sebuah protein raksasa, panjangnya lebih dari 1 µm,[3] fungsinya yaitu sebagai mata air molekuler yang bertanggung jawab atas elastisitas pasif otot. Protein ini terdiri dari 244 domain protein terlipat secara individual yang dihubungkan dengan urutan peptida yang tidak terstruktur.[4] Domain ini terbuka saat protein diregangkan dan terlipat kembali saat ketegangan dihilangkan.[5]

Titin berperan penting dalam kontraksi jaringan otot lurik. Protein ini menghubungkan garis Z ke garis M di dalam sarkomer. Protein ini berperan memaksa transmisi pada garis Z dan ketegangan istirahat di area Pita I.[6] Protein ini membatasi jangkauan gerak sarkomer ketika dalam kondisi tegang, sehingga berkontribusi terhadap kekakuan pasif otot. Variasi dalam urutan titin antara berbagai jenis otot (mis., Jantung atau kerangka) telah berkorelasi dengan perbedaan sifat mekanik otot-otot ini.[1][7]

Titin adalah protein paling banyak ketiga yang ada dalam otot (setelah myosin dan actin), tubuh manusia dewasa paling tidak mengandung sekitar 0,5 kg titin.[8] Dengan panjang ~27.000 sampai ~33.000 asam amino (tergantung pada sambatan isoform), titin adalah protein terbesar yang diketahui.[9] Lebih jauh lagi, gen titin mengandung jumlah terbesar exon (363) yang ditemukan pada gen tunggal manapun,[10] serta ekson tunggal terpanjang (17.106 bp).

Penemuan

Reiji Natori pada tahun 1954 adalah orang pertama yang mengusulkan struktur elastis pada serat otot sebagai penyebab kembalinya otot ke keadaan istirahat saat otot-otot diregangkan dan kemudian dilepaskan.[11] Pada tahun 1977, Koscak Maruyama dan rekan kerja mengisolasi protein elastis dari serat otot, yang mereka sebut connectin.[12] Dua tahun kemudian, Kuan Wang dan rekan kerjanya mengidentifikasi pita dobel pada gel elektroforesis yang sesuai dengan protein elastis dengan berat molekul tinggi, yang mereka beri nama titin.[13][14]

Labeit pada tahun 1990 mengisolasi sebagian cDNA kloning titin.[2] Pada tahun 1995, Labeit dan Kolmerer menentukan urutan cDNA dari titin jantung manusia.[4] Bang and colleagues in 2001 determined the complete sequence of the human titin gene.[10][15]

Genomik

Gen manusia yang mengkodekan titin terletak pada lengan panjang kromosom 2 dan mengandung 363 ekson, yang bersama-sama mengkodekan 38.138 residu (4200 kDa).[10] Dalam gen tersebut ditemukan sejumlah besar eksplan PEVK yang berjumlah 84 sampai 99 nukleotida yang memperjelas motif residu 28 sampai 33-residu yang dapat mewakili unit struktural dari pegas PEVK titin. Jumlah motif PEVK dalam gen titin tampaknya meningkat selama evolusi, yang tampaknya memodifikasi daerah genom yang bertanggung jawab untuk sifat pegas titin.[16]

Isoform

Sejumlah isoform diproduksi di jaringan otot lurik yang berbeda sebagai hasil dari sambungan alternatif.[17] Semua kecuali satu dari isoform ini berada dalam kisaran ~27.000 sampai ~36.000 residu asam amino. Pengecualian adalah inoform jantung kecil novex-3 yang hanya 5.604 residu amino panjangnya. Tabel berikut mencantumkan isoform titin yang diketahui:

Isoform alias/deskripsi panjang MW
Q8WZ42-1 The "canonical" sequence 34,350 3,816,030
Q8WZ42-2 34,258 3,805,708
Q8WZ42-3 Small cardiac N2-B 26,926 2,992,939
Q8WZ42-4 Soleus 33,445 3,716,027
Q8WZ42-5 32,900 3,653,085
Q8WZ42-6 Small cardiac novex-3 5,604 631,567
Q8WZ42-7 Cardiac novex-2 33,615 3,734,648
Q8WZ42-8 Cardiac novex-1 34,475 3,829,846
Q8WZ42-9 27,118 3,013,957
Q8WZ42-10 27,051 3,006,755
Q8WZ42-11 33,423 3,713,600
Q8WZ42-12 35,991 3,994,625
Q8WZ42-13 34,484 3,831,069

Struktur

Titin adalah protein terbesar yang diketahui; varian manusianya terdiri dari 34.350 asam amino, dengan berat molekul isoform "kanonik" dewasa dari protein sekitar 3.816.188,13 Da.[18] Homolog protein ini pada tikus bahkan lebih besar lagi, terdiri dari 35.213 asam amino dengan MW 3.906.487,6 Da.[19] Protein ini memiliki titik isoelektrik teoritis 6,01.[18] Rumus kimia empiris proteinnya adalah C169,719H270,464N45,688O52,237S911.[18] Ini memiliki teori indeks ketidakstabilan (II) 42,41, dan karena itu diklasifikasikan sebagai protein tidak stabil.[18] Paruh waktu protein in vivo, waktu yang dibutuhkan setengah dari jumlah protein dalam sel untuk dipecah setelah sintesisnya di dalam sel, diperkirakan sekitar 30 jam (pada reticulocyte mamalia).[17]

Protein titin terletak di antara filamen tebal myosin dan cakram Z.[20] Titin terdiri dari rangkaian linear dua jenis modul (juga disebut sebagai domain protein; 244 total salinan): tipe I (domain fibronektin tipe III; 132 salinan) dan tipe II (domain imunoglobulin; 112 salinan).[4] This linear array is further organized into two regions:

  • N-terminal I-band: acts as the elastic part of the molecule and is composed mainly of type II modules. More specifically the I-band contains two regions of tandem type II immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine.[20] PVK elasticity has both entropic and enthalpic origins characterizable by a polymer persistence length and a stretch modulus.[21] At low to moderate extensions PEVK elasticity can be modeled with a standard wormlike chain (WLC) model of entropic elasticity. At high extensions PEVK stretching can be modeled with a modified WLC model that incorporates enthalpic elasticity. The difference between low-and high- stretch elasticity is due to electrostatic stiffening and hydrophobic effects.
  • C-terminal A-band: is thought to act as a protein-ruler and possesses kinase activity. The A-band is composed of alternating type I and II modules with super-repeat segments. These have been shown to align to the 43 nm axial repeats of myosin thick filaments with immunoglobulin domains correlating to myosin crowns.[22]

Function

 
Sliding filament model of muscle contraction. (Titin labeled at upper right.)

Titin is a large abundant protein of striated muscle. Titin's primary functions are to stabilize the thick filament, center it between the thin filaments, prevent overstretching of the sarcomere, and to recoil the sarcomere like a spring after it is stretched.[23] An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle-associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes.[24][25] Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Of the many titin variants identified, five are described with complete transcript information available.[1][2]

Titin interacts with many sarcomeric proteins including:[10]

Clinical relevance

Mutations anywhere within the unusually long sequence of this gene can cause premature stop codons or other defects. Titin mutations are associated with hereditary myopathy with early respiratory failure, early-onset myopathy with fatal cardiomyopathy, core myopathy with heart disease, centronuclear myopathy, Limb-girdle muscular dystrophy type 2J, familial dilated cardiomyopathy 9,[6][26] hypertrophic cardiomyopathy and tibial muscular dystrophy.[27] Further research also suggests that no genetically linked form of any dystrophy or myopathy can be safely excluded from being caused by a mutation on the TTN gene.[28] Truncating mutations in dilated cardiomyopathy patients are most commonly found in the A region; although truncations in the upstream I region might be expected to prevent translation of the A region entirely, alternative splicing creates some transcripts that do not encounter the premature stop codon, ameliorating its effect.[29]

Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.[24]

Interactions

Titin has been shown to interact with:

Linguistic significance

The name titin is derived from the Greek Titan (a giant deity, anything of great size).[13]

As the largest known protein, titin also has the longest IUPAC name of a protein. The full chemical name of the human canonical form of titin, which starts methionyl... and ends ...isoleucine, contains 189,819 letters and is sometimes stated to be the longest word in the English language, or any language.[41] However, lexicographers regard generic names of chemical compounds as verbal formulae rather than English words.[42]

See also

Referensi

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  3. ^ Eric H. Lee. "The Chain-like Elasticity of Titin". Theoretical and Computational Biophysics Group, University of Illinois. Diakses tanggal 25 September 2014. 
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  7. ^ Online Mendelian Inheritance in Man (OMIM) [1]
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  15. ^ Online Mendelian Inheritance in Man (OMIM) -188840
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Bacaan lanjutan

  • Tskhovrebova L, Trinick J (September 2003). "Titin: properties and family relationships". Nature Reviews Molecular Cell Biology. 4 (9): 679–89. doi:10.1038/nrm1198. PMID 14506471. 
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  • Kolmerer B, Witt CC, Freiburg A, Millevoi S, Stier G, Sorimachi H, Pelin K, Carrier L, Schwartz K, Labeit D, Gregorio CC, Linke WA, Labeit S (1999). "The titin cDNA sequence and partial genomic sequences: insights into the molecular genetics, cell biology and physiology of the titin filament system". Reviews of Physiology, Biochemistry and Pharmacology. 138: 19–55. doi:10.1007/BF02346659. PMID 10396137. 
  • Trinick J, Tskhovrebova L (October 1999). "Titin: a molecular control freak". Trends in Cell Biology. 9 (10): 377–80. doi:10.1016/S0962-8924(99)01641-4. PMID 10481174. 
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  • Tskhovrebova L, Trinick J (February 2002). "Role of titin in vertebrate striated muscle". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 357 (1418): 199–206. doi:10.1098/rstb.2001.1028. PMC 1692937  . PMID 11911777. 
  • Sela BA (July 2002). "[Titin: some aspects of the largest protein in the body]". Harefuah. 141 (7): 631–5, 665. PMID 12187564. 
  • Tskhovrebova L, Trinick J (November 2004). "Properties of titin immunoglobulin and fibronectin-3 domains". The Journal of Biological Chemistry. 279 (45): 46351–4. doi:10.1074/jbc.R400023200. PMID 15322090. 
  • Wu Y, Labeit S, Lewinter MM, Granzier H (December 2002). "Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM". Journal of Cardiac Failure. 8 (6 Suppl): S276–86. doi:10.1054/jcaf.2002.129278. PMID 12555133. 

Pranala luar

 
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