Group:MUZIC:Titin

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Contents

Introduction

Sequence annotation

The giant protein titin (also called „connectin“ by Maruyama et al., 1977 [1] [2]) is the largest known protein which is composed of 38138 amino acid residues (see Uniprot for Q8WZ42). The human titin gene is located on chromosome 2q31, is 294 kilobases large and contains 363 exons (see gen information at TTN titin). Its molecular weight varies from 1,5 MegaDalton to ~3,7 MegaDalton in numerous isoforms. These isoforms are produced by alternative splicing which occurs mostly in the I-band region of titin. For example, the following predominant titin isoforms are found in human heart : the N2B-isoform (3,000 kDa) – 65%, which contains N2B element composed of 3 Ig domains and a central ~570 a.a. unique sequence, and N2BA-isoforms (~3,200–3,700 kDa) - 35%. Titin is the third most abundant protein in striated muscle cells after actin and myosin. It forms the so called “third filament system”. Single titin macromolecules have a length >1-μm and span from the Z-disk to M-line through the half-sarcomere. The main function of titin is to provide passive tension which helps to restore the length of the resting sarcomere after contractile activity. However, titin has other important functions: it acts as a molecular ruler/scaffold, determining the correct location of various muscle proteins. Titin also serves as a nodal point in signaling cascades within thesarcomere, takes part in sarcomere formation and maintenance. It is also worth mentioning that set of titin-like proteins is expressed in non-muscular tissues and a distinct titin isoform of ~1 MDa can be found in human smooth muscle tissues (280 of 363 existing exons are excluded ). 90 % of titin is composed of immunoglobulin (Ig) domains [3], PEVK motifs and fibronectin-type-III (FN3)-like [4] domains [5].
The Ig-domain is usually ~ 100 amino acid residues large and consists of two β-sheets that create a two-layered elongated fold. Majority of Ig-domains of muscle proteins belong to so calles I-set subfamily. N- and C-termini of the Ig-fold are located at the opposite ends of structure and, thus, a protein, composed mainly of Ig-domains resembles beads on a string. Molecular elasticity of such proteins is created by stretching of interdomain linkers or by unfolding of domains themselves [6] [7].
The fibronectin type III domain has an average size of ~100 amino acids residues and adopts a β-sandwich structure. Currently several structures of FN III domains from the A-band part of titin are deposited in the “Protein Data Bank”. They are: structure of domain A71 [8], structure of FnIII tandem A77-A78 [9], Ig(A168)-Ig(A169)-FnIII(A170) [10].
Among the structural elements of titin, the Ig-domains are most resistant to mechanical unfolding. The slightly weaker FN III domains are located in the A-band portion of the titin, which is stabilized additionally by interactions with the thick filaments. Of note, Ig-domains that are located in the I-band differ in their stability. Domains that are located close to the Z-disk show unfolding forces of approximately 150 pN, central Ig-domains unfold around ~200 pN, while Ig-domains that are located closely to the A-bandunfold around ~ 250 pN. Thus, titin unfolding caused by muscle stretch should start close to the Z-disk and continue towards the A-band part of molecule. [11]
PEVK repeats are ~28-residues disordered motifs enriched in proline, glutamine, valine, lysine which are important for the entropic (rubber-like) elasticity of titin. Due to the large size of titin, this entry is mainly focused on the Z-disk portion of titin.

Schematic domain structure

Concisely annotated schemes of titin's domain structure can also be found in Labeit et al., 2006 [12], domain arrangement and interacting proteins are concisely described in Kontrogianni-Konstantopoulos et al., 2009 [13] and Linke, 2007 [14].

Structure of full length telethonin in complex with the N-terminus of titin.


The Z-disk fragment of titin

Approximately 2000 residues of titin’s amino-terminus, coded by exons 1–28, is localized within the Z-disk. This region consists of immunoglobulin-type domains, proline-rich ZIS region and a variable number of unique 45-residue motifs called Z-repeats [15] These repeats are located between Ig-domains 2 and 3. Each of them share ~50% sequence homology. The N-terminal immunoglobulin domains Z1-Z4 are present in all isoforms of titin, whereas number of Z-repeats varies from 2 to 7 in different types of striated muscles because of differential splicing [16] . Both repeats 1 and 7 are present in all isoforms except smooth muscle titin.


Structures

3D structures of N-terminal part of titin or its complexes, deposited in "Protein Data Bank"


PDB ID Structure PubMed link
2F8V Structure of full length telethonin in complex with the N-terminus of titin PMID 16713295
2A38 Crystal structure of the N-Terminus of titin PMID 16962974
1YA5 Crystal structure of the titin domains z1z2 in complex with telethonin PMID 16407954
1H8B EF-hands 3,4 from alpha-actinin / Z-repeat 7 from titin PMID 11573089


2F8V -This structure shows a complex of titin N-terminus with full-length telethonin at 2.75 Ǻ resolution. Data, complementary to the structure, show formation of a dimer of 2 titin/telethonin complexes and possibly formation of higher oligomers.
2A38 - This structure shows two Ig-domains, Z1Z2, from amino-terminus of titin at 2 Ǻ resolution. It proves that Z1Z2 moiety adopts semiextended conformation with certain rigidity and limited dynamics.
1YA5 - This structure shows the assembly of titin’s two N-terminal Ig-domains with the Z-disk protein telethonin (residues 1 to 90) at 2.44 Ǻ resolution. It also proposes a model for crosslinking of actin filaments.
1H8B - This structure shows a complex of Calmoduline-like calcium insensitive EF-hand domain of α-actinin and Z-repeat 7 of titin solved by solution NMR.



Function and interactions

Titin acts as the tension sensor in muscle cells. As mentioned in the "Sequence annotation", titin molecules extend through the whole half-sarcomere, thus, they have a proper position for detecting the sarcomere’s contraction and transfering correponding signals.The N-termins of titin is attached to the actin filaments at the Z-disk and and connected to the myosin filament in the A-band/M-band. Specific parts of titin can sense mechnaical forces generated by the sarcomere during stretch/contraction. Transmission of these signals is possible because of titin’s interactions with other sarcomeric proteins. To date, approximately 20 different proteins are known to interact with titin at so called “hot spots” along the entire molecule and to participate in signal transduction. For example, titin interacts with myosin heavy chain and myosin-binding protein-C in the A band and with myomesin, obscurin, FHL1, calpain-3, nbr1 and MURFs at the M band [17]
The atomic structure of the Z1Z2 Ig-domain doublet of titin's N-terminus was determined by Zou et al., 2006.[18]. The conformational features were thoroughly analyzed in a comprehensive study that combined X-ray crystallography, SAXS, N15 relaxation NMR, residual dipolar couplings [19] . It was shown that Z1Z2 adopts a semi-extended conformation in solution, which is in agreement with crystallographic data. Surprisingly, it was shown that the dynamics of the Ig-doublet is rather restricted despite the presence of long interdomain linker and absence of contacts between Ig domains. NMR experiments further showed absence of movements of the linker moiety and an overall semi-rigid state of the structure. These data agree with NMR studies of I91–I92 and may be considered a general model of the conformational state of Ig-doublets along the titin filament.

At the N-terminal end of titin Ig-domains Z1/Z2 interact with small 19 kDa protein, called telethonin [20] [21](also called “T-Cap”). It connects titin molecules, according to current models from same half of the sarcomere, into an antiparallel “sandwich”. This complex has 2:1 stoichiometry, which means that one telethonin molecule allows an antiparallel arrangement of two titin molecules.Due to numerous hydrogen bonds that connect the β-strands of two molecules, the titin-telethonin complex is extremely resistant to mechanical forces along one axis of the complex. Telethonin is thus likely to be responsible for anchoring titin molecules in the Z-disc. It has also been proposed to play a role as a mechanosensor, as well as participating in targeting other sarcomeric proteins. For example, telethonin seems to be connected to membrane-associated proteins like small ankyrin-1 (sANK1) and the potassium channel subunit minK [22], that are localized in the sarcoplasmic reticulum and T-tubules, respectively. In turn, small-ankyrin-1 is associated with spectrin, desmin and obscurin. It was proposed that indirect interactions of small ankyrin with the titin amino-terminus promote correct positioning of the sarcoplasmic reticulum (SR) around the Z-disc. Titin could also participate in SR organization via the interaction of Ig-like domains Z8/Z9 with obscurin [23]. Binding of telethonin to minK would place T-tubules in proximity of the Z-disc and might influence functioning of potassium channel depending on myocyte stretch. However, minK is not expressed in skeletal muscle (where T-tubules are localized at the A/I junction) or ventricular myocytes [24], therefore this proposed mechanism is unlikely to be of general relevance. Telethonin was also shown to interact the TGF-beta related growth factor myostatin and the calcineurin inhibitor calsarcin-3. Finally, the NH2-terminus of titin was reported to interact via telethonin with muscle LIM protein (MLP or CSRP3). In striated muscles, MLP localizes partly to the Z-disc, however it is found also at costameres, in the I-band and in the nucleus. Translocation of MLP to the nucleus may co-regulate myogenic transcription factors and upregulate protein expression. Another related cascade, the “Telethonin-MLP-calcineurin- nuclear factor of activated T cells (NFAT)” signaling pathway is implicated in mechanosensing and leads to physiological hypertrophy. It has been proposed that mechanical stress on the Z-disc activates this signaling cascade, however, the precise mechanism of signal transduction and the role of titin domains Z1/Z2 remain to be investigated.Another telethonin-mediated interaction of titin’s amino terminus is with MDM2 (mouse double minute-2). This protein is an E3 ubiquitin ligase that ubiquitylates the tumor suppressor p53/TP53, leading to its proteasomal degradation. Other sites of titin mechanosensing, not resident in the Z-disc, include the MARP-Myopalladin complex that interacts with titin's N2A-domain in the I-band and the nbr1 complex interacting with the titin kinase domain at the M-band. Interaction with actin was reported for titin's domains Z9-I1. Additional binding partners of titin at the Z-disc are nebulin and filamin C, which both interact direct with titin by their carboxy-terminal parts.

Essential interactions of α-actinin and the Z-repeats of titin within Z-disc were shown experimentally [25] [26] [27]. This interaction was reported for Z-repeats 1 and 7 and the calmodulin-like domains (syn. EF-hand domains) at the C-terminus of α-actinin. A third of interaction site is located between Z-repeat 7 and the adjacent Ig-domain of titin and involves the spectrin-like domains 2 and 3 of the α-actinin homodimer. Strong interactions between actin, α-actinin and titin form a spatial scaffold, thus enabling the correct placement of other proteins inside the Z-disc. In addition, it was also shown that two muscle proteins, LIM and FATZ, are interacting with both telethonin and α-actinin, reinforcing the titin/telethonin and titin/α-actinin networks. The Z-disk connects all elastic and contractile components of sarcomere and enables transduction of tensile forces. Some of these components take part in different signaling pathways, others are responsible for direct mechanosensing. Within the Z-disk several layers of actin crosslinked by α-actinin are usually visible on electron microscopy images. The thicker is the Z-disk, the more layers it has.

The Z- disc thus connects major elastic and contractile components of the sarcomere and enables the transduction of active and passive forces along actin and titin filaments, respectively. Some of these components take part in different signaling pathways, others are responsible for direct mechanosensing. Within the Z-disc, several layers of actin crosslinks by α-actinin are visible in electron microscopy images. The thicker is the Z-disc, the more layers it has. The thickness of Z-discs varies significantly between different types of muscles due to adaptation to variable levels of mechanic stress. It was proposed that titin Z-repeats are the major determinant of Z-disc thickness. The number of Z-repeats and the number of crosslink layers in the Z-disc correlate tightly (i.e. sarcomeres with the full range of Z-repeats have the thickest disc, and the chicken pectoralis Z-disc with only 2 layers of crosslinks has only two Z-repeats, [28]). However, major questions about the ultrastructure and molecular assembly of the Z-disc remain, as it appears that the length of a single repeat may be less than the thickness of single layer inside Z-disc (19 nm). Clearly, highly resolved ultrastructural analysis avoiding the problem of EM sample shrinkage will be needed to complement the structure of individual Z-disk protein complexes.
An additional non-canonical function of NH2-terminus of titin that was proposed recently. Studies of mammalian non-muscle cell cultures suggested a nuclear localization of the amino-terminal region of titin. Immunofluorescence microscopy has shown that Z1-Z2-Zr moiety of titin can be transported into the nucleus. A functional nuclear localization signal (NLS) at residues 200-PAKKTKT-206 was identified by screening of titin constructs of various length. This finding was confirmed in the following cell lines: human MG-63 and baby hamster kidney BHK-21, mouse MC3T3-E1, COS-7. It was shown that mutation (Lysin203 to Alanine) in this region leads to the loss of NLS’ function and results in cytoplasmic localization of Z1-Z2-Zr.
In contrast to sarcomeres, within non-muscle cells titin doesn’t form an ordered network of fibrils, but has rather a “punctate pattern” of distribution both in the nucleus and cytoplasm. Using human osteoblast cells, MG-63, it was shown that overexpression of titin Z1-Z2-Zr domain leads to change of cell shape (from spindle-like to rounded), decreases contact inhibition of cells and facilitates cell proliferation. Proposed mechanism of action involves activation of Wnt/β-catenin pathway. This signaling cascade is important for proper bone maintenance, Z1-Z2-Zr part of titin may participate in remodeling of bone tissue. [29] However, given the otherwise tight myogenic regulation of titin and the fact that titin antibodies around the Z-disk do not stain nuclei even in muscle, the relevance of these cell culture observations to titin physiological findings remain to be established. A list of proteins that directly interact with the Z-disc portion of titin and their functions are given in the table below (see minireview of Kruger and Linke, 2011. 2011. [30])

Binding partners of titin within the Z-disk


Titin region Interacting partner Suggested function
Z1-Z2 Telethonin (Tcap) Connects NH2 termini of two titin filaments from

same half-sarcomere; forms putative stretch sensor complex with MLP

Z1-Z2 Small Ankyrin-1 May help position the sarcoplasmic reticulum near

the Z-disk region

Z2-Zis-1 γ-Filamin Links titin to integrin and focal adhesion complex
Z2-Zis-1 Nebulin/Nebulette Stabilization of cytoskeletal linkages to the Z-disk
Zis-1; Z-repeats; Zis-2 α-Actinin Anchors titin's NH2-terminus in the Z-disk;provides Z-disk stability
Z8/Z9 Obscurin Anchorage to the sarcoplasmic reticulum via small ankyrin ank1.5. Links to GTPase signaling via C-terminal GEF domain.
Z9/I1 Actin Connects titin to thin filaments at the N1-line of

the sarcomere



Pathology

Titin mutations cause various muscle pathologies. Detailed information about titin’s gene structure and whole-genome sequencing approaches allows linking mutations with their phenotypical consequences. For example, truncating mutations in titin appear to be extremely common and cause dilated cardiomyopathy(DCM) [31] [32] was shown for exons 18 and 326. A mutation in exon 326 leads to expression of truncated form of titin (~2 mDa) which is sensitive to proteolysis. Mutation in exon 18 causes disruption of the normal fold of the encoded Ig- domain, which in turn affects the function of entire titin.
Recent studies showed that mutations in exon 363 cause tibial muscular dystrophy [33] and a mutation in exon 363. These mutations also affect the fold of an Ig-domain (M10) and disrupt the interaction of titin with the obscurin-myomesin complex. Moreover, disease-causing mutations in titin exons 2, 14 and 49 were identified by massive sequencing approaches. The first and the second mutation seem to affect the interactions between titin and its ligands inside the Z-disc (decreased affinity to T-Cap and α-actinin, correspondingly). Studies of Kimura et al.[34], ppropose that a significant percentage of cardiomyopathies may be caused by titin mutations. This is underscored by recent next-generation sequencing in patients with DCM. It is worth mentioning that microscopy studies of cardiac hypertrophy and degeneration have shown significant downregulation of titin expression. Reduced titin levels may cause decreased elasticity of cardiomyocytes in failing hearts [35], as altered titin elasticity has been linked to congenital heart diseases [36]. It is worth mentioning specifically the mutations directly related to the Z-disc part of titin. The Val54Met point mutation in domain Z1 seems to lead to decreased binding to telethonin. Mutation in Z-repeat 7 of Ala743 to Val seems to affect the interaction with α-actinin, while point mutation of Ala740 to Leu was reported to have the opposite effect [37]. A missense mutation in Z4 (Trp930 to Arg) is predicted to destroy the Ig-domain fold.


References:

  1. Maruyama K. (1997) Connectin/titin, giant elastic protein of muscle. FASEB J. 11(5):341-5. PMID 9141500
  2. Maruyama K. (1994) Connectin, an elastic protein of striated muscle. Biophys Chem. 50(1-2):73-85 PMID 8011942
  3. about Immunoglobulin fold see also http://www.ncbi.nlm.nih.gov/books/NBK22461/ and http://smart.embl.de/smart/do_annotation.pl?DOMAIN=SM00409
  4. description of Fibronectin type 3 domain see at http://smart.embl.de/smart/do_annotation.pl?DOMAIN=SM00060
  5. Labeit S, Kolmerer B. (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science. 270(5234):293-6. PMID 7569978
  6. von Castelmur E, Marino M, Svergun DI, Kreplak L, Ucurum-Fotiadis Z, Konarev PV, Urzhumtsev A, Labeit D, Labeit S, Mayans O. (2008) A regular pattern of Ig super-motifs defines segmental flexibility as the elastic mechanism of the titin chain. Proc Natl Acad Sci U S A. 105(4):1186-91. Epub 2008 Jan 22. PMID 18212128
  7. Linke WA. (2000) Stretching molecular springs: elasticity of titin filaments in vertebrate striated muscle. Histol Histopathol. 15(3):799-811. PMID 10963124
  8. Goll CM, Pastore A, Nilges M. (1998) The three-dimensional structure of a type I module from titin: a prototype of intracellular fibronectin type III domains. Structure. 6(10):1291-302. PMID 9782056
  9. Bucher RM, Svergun DI, Muhle-Goll C, Mayans O. (2010) The structure of the FnIII Tandem A77-A78 points to a periodically conserved architecture in the myosin-binding region of titin. J Mol Biol. 401(5):843-53. Epub 2010 Jun 11. PMID 20542041
  10. Mrosek M, Labeit D, Witt S, Heerklotz H, von Castelmur E, Labeit S, Mayans O. (2007) Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin. FASEB J. 21(7):1383-92. Epub 2007 Jan 10.PMID 17215480
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  13. Kontrogianni-Konstantopoulos A, Ackermann MA, Bowman AL, Yap SV, Bloch RJ. (2009) Muscle giants: molecular scaffolds in sarcomerogenesis. Physiol Rev. 89(4):1217-67.PMID 19789381
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  15. Gautel M, Goulding D, Bullard B, Weber K, Fürst DO. (1996) The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers. J Cell Sci. 109 ( Pt 11):2747-54. PMID 8937992
  16. Peckham M, Young P, Gautel M. (1997) Constitutive and variable regions of Z-disk titin/connectin in myofibril formation: a dominant-negative screen. Cell Struct Funct. 22(1):95-101. PMID 9113395
  17. Lange S, Ehler E, Gautel M. (2006) From A to Z and back? Multicompartment proteins in the sarcomere. Trends Cell Biol. 16(1):11-8. Epub 2005 Dec 6. PMID 16337382
  18. Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M. (2006) Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature. 439(7073):229-33. PMID 16407954
  19. Marino M, Zou P, Svergun D, Garcia P, Edlich C, Simon B, Wilmanns M, Muhle-Goll C, Mayans O. (2006) The Ig doublet Z1Z2: a model system for the hybrid analysis of conformational dynamics in Ig tandems from titin. Structure. 14(9):1437-47. PMID 16962974
  20. Pinotsis N, Petoukhov M, Lange S, Svergun D, Zou P, Gautel M, Wilmanns M. (2006) Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus. J Struct Biol. 155(2):239-50. Epub 2006 Apr 27.PMID 16713295
  21. see http://www.uniprot.org/uniprot/O15273
  22. see http://www.uniprot.org/uniprot/P15382
  23. see http://www.uniprot.org/uniprot/Q5VST9
  24. Kupershmidt S, Yang T, Anderson ME, Wessels A, Niswender KD, Magnuson MA, Roden DM. (1999) Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circ Res. 84(2):146-52. PubMed PMID 9933245.
  25. Ohtsuka H, Yajima H, Maruyama K, Kimura S. (1997) Binding of the N-terminal 63 kDa portion of connectin/titin to alpha-actinin as revealed by the yeast two-hybrid system. FEBS Lett. 401(1):65-7. PMID 9003807
  26. Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA, Suzuki K, Labeit S. (1997) Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. J Mol Biol. 270(5):688-95 PMID 9245597
  27. Atkinson RA, Joseph C, Kelly G, Muskett FW, Frenkiel TA, Nietlispach D, Pastore A. (2001) Ca2+-independent binding of an EF-hand domain to a novel motif in the alpha-actinin-titin complex. Nat Struct Biol. 8(10):853-7. PMID 11573089
  28. Peckham M, Young P, Gautel M. (1997) Constitutive and variable regions of Z-disk titin/connectin in myofibril formation: a dominant-negative screen. Cell Struct Funct. 22(1):95-101.PMID 9113395
  29. Qi J, Chi L, Labeit S, Banes AJ. (2008) Nuclear localization of the titin Z1Z2Zr domain and role in regulating cell proliferation. Am J Physiol Cell Physiol. 295(4):C975-85. Epub 2008 Aug 6.PMID 18684985
  30. Krüger M, Linke WA. (2011) The giant protein titin: a regulatory node that integrates myocyte signaling pathways. J Biol Chem. 286(12):9905-12. Epub 2011 Jan 21. PMID: 21257761
  31. Dilated cardiomyopathy http://www.nlm.nih.gov/medlineplus/ency/article/000168.htm
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  33. Tibial muscular dystrophy http://ghr.nlm.nih.gov/condition/tibial-muscular-dystrophy
  34. Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A. (2002) Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun. 291(2):385-93. PMID 11846417
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Third filament diseases. 19181097 Zaspopathy in a large classic late-onset distal myopathy family. 17337483 The Z-disk diseases. 19181098


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