Titin (TTN) is the largest known protein. The human TTN contains 34,350 residues. It is responsible for the passive elasticity of muscle. It has 244 domains connected by unstructured regions. The domains unfold when TTN is stretched. (1ya5). Additional details in
Introduction
Titin, also known as connectin, is an elastic and approximately 3,6 MDalton large protein which assembles itself to protein filaments. It is made of more than 30000 amino acids and includes 320 protein domains and therefore is known as the largest human protein.
It is a part of the sarcomere, the smallest functional unit in the striated muscles. Tintins task in the sarcomere is to center the myosinheads between the actin filaments and to re-establish the unstreched mode.
The titin filament together with the actin filament is connected mechanically over the alpha-actinin with the z-disk. This bond is relatively weak and well regulateable, this is a necessary precondition for the unhindered contraction mechanism. Additionally titin binds to telethonin (t-cap) in the region of the z-disk. In the region of the A-band titin is accumulated with its stiff end near the myosin filament and binds to the calcium dependable protease calpain.
In the region of the I-band the long polypeptide becomes elastic and can be turned. The assembly of titin differs in the skeletal- and the cardiac muscle, whereby the marginal expandability of the cardiac sarcomer can be explained.
The titin filament is not facilitated with the muscle contraction; it just participates in the flexibility and stability of the muscle and helps to define the contraction speed. In addition, titin is responsible for the relaxing mode of the muscle.
Z1Z2 stretched unstretched
z1z2 / Telethonin complex
Titin, the third most abundant and largest known protein with a lenght > 1 μm, is made of more than 300 tandem repeats of immunoglobulin-like (Ig) domains, fibronectin type (FN-III) repeats and from flexible random coil-like PEVK which are rich in proline, glutamate, valine and lysine regions. The insertion of single Lg-domains lead to isoforms of titin that can be found in the cardiac and skeletal muscles.
The N-terminal part of titin interacts with some sarcomeric proteins at the Z-disc. These interactions maintain structural assistance for the development and function of myofibrils and also have regulatory influence, such as responding to stretching forces developed in titin. Unique among them, is the structural protein telethonin, which is believed to anchor the ends of two separate titin molecules to the Z-disc. The C-terminal region is a part of the sarcomeric M-line.
In picture (Z1Z2 stretched unstretched) one can see the highly schematic view of the tertiary structure elasticity of titin due to bending adjacent protein domains open and closed. In real titin, not every linker may contribute high flexibility, some linkers might be short and stiff.
Extensive studies have shown that titin acts in many ways. Titin is believed to be a molecular scaffold in the early growth of myofibrill and that its end is not just an anchor, furthermore they interact with signaling proteins at the Z-line and M-line. It also functions as a molecular spring that dampens sarcomeric extension forces.
The I-band region, that forms an elastic connection between the ends of thick filaments and the sarcomeric Z-disc, contains flexible PEVK domains interdigitated between Ig-domain repeats. These random coil PEVK domains are believed to reversibly unfold to permit the extension, like an entropic spring, and to contribute to titin elasticity when weak forces (50 pN) are applied.
Titin has soft elasticity regions which are followed by stiffer, nonlinear regions of elasticity. The soft elasticity regions are a generic behavior of random coils formed through PEVK and similar domains and also because of straightening out of titin's multidomain segments. The stiffer elasticity is due to individual domains. Strong forces (160 pN) on titin unravels its secondary structure.
Adjacent segments may exhibit a flexibility that leads a titin chain to assume in the relaxed state, a locally compacted shape and a straight shape when under tension.
As seen in the image (Z1Z2 / Telethonin complex), the major force enduring component of this complex is an elaborate intermolecular hydrogen bonding network formed across among telethonin and Z1Z2 domains, and not intramolecularly among termini β-strands of individual Z1 or Z2 domains. This shift to a stronger force enduring interface reduces the possibility of unraveling the individual Ig-domains, thus stabilizing the complex. This demonstrates how cross-linking via hydrogen bonds serves as an important mechanism. It functions as a molecular adhesive, increasing the ability of protein complexes to resist against mechanical stress.
3D Structures of Titin
Updated on 27-June-2017
2a38 - hTTN residues 1-194 - human
2f8v, 1ya5 - hTTN residues 1-196+telethonin
1g1c - hTTN residues 2027-2125
4qeg - hTTN I10 residues 2880-2967
1tit, 1tiu- hTTN I27 residues 5253-5341 – NMR
5joe - hTTN I81 residues 9582-9671
2rq8 – hTTN residues 12677-12765 (mutant) – NMR
1waa - hTTN residues 12801-12889
4o00 - hTTN residues 14217-14319
1bpv – hTTN A71 residues 14859-14961 – NMR
3lpw – hTTN A77-A78 residues 22877-23070
2j8h, 2j8o, 2ill – hTTN residues 24430-24623
1tki – hTTN serine kinase fragment residues 24748-25068
2bk8 – hTTN residues 25073-25166
1nct, 1ncu – hTTN M5 residues 26059-26155 – NMR
1tnm, 1tnn – hTTN M5 residues 26059-26155
3lcy – hTTN A164-A165 residues 31456-31649
2nzi – hTTN residues 31854-32155
4jnw - hTTN residues 32172-32492
3qp3 – hTTN M4 residues 33294-33395
3puc – hTTN M7 residues 33774-33871
2y9r, 3q5o – hTTN M10 residues 34252-34350
2wp3, 2wwm, 3knb – hTTN M10 residues 34252-34350 +obscurin-like protein 1 fragment
2wwk - hTTN M10 residues 34252-34350 +obscurin-like protein 1 fragment (mutant)
4c4k, 4uow - hTTN M10 residues 34252-34350 +obscurin IG domain
2rik – rTTN I67-I69 – rabbit
2rjm - rTTN I67-I69 (mutant)
3b43 - rTTN I65-I70
1h8b – rTTN residues 648-698+h α Actinin 2 EF hands 3&4
Additional Resources
See: Titin Structure & Function for additional information
See Also
http://www.biophysik.physik.uni-muenchen.de/movies/movies-and-animations
