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  • Review Article
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Titin: properties and family relationships

Nature Reviews Molecular Cell Biology volume 4, pages 679–689 (2003)Cite this article

Key Points

  • Titin is the largest known protein (∼3 MDa) and consists principally of ∼300 immunoglobulin and fibronectin domains. Pairs of its string-like molecules are arranged in an antiparallel manner to span the entire sarcomere in vertebrate striated muscle (∼2 μm), with their amino- and carboxy-terminal ends in the Z- and M-lines, respectively.

  • More than half of the titin molecule is attached to the thick filament, where it might control the exact assembly of myosin and other filament components. Between the end of the thick filament and the Z-line, titin forms elastic connections; these are the main source of passive elasticity in muscle, with isoforms varying widely in size and compliance in muscles of different stiffness.

  • Titin elasticity has been studied in situ (for instance, by monitoring epitope movement) and in individual molecules (using new single-molecule techniques, such as optical tweezers and atomic-force spectroscopy). The elastic mechanism initially involves straightening the molecule, followed by unfolding of the polypeptide chain; this occurs first in the small PEVK region, in which the secondary structure is not well understood.

  • Near the middle of the thick filament, titin has a kinase domain, but the functions and substrate(s) are not fully understood. Both ends of the molecule have potential phosphorylation sites that are likely to be involved in signalling, assembly and turnover mechanisms. Invertebrate muscles contain no exact homologue of titin that spans half the sarcomere. Instead, there is a range of smaller molecules in different parts of the sarcomere, reflecting the greater structural and functional diversity of invertebrate muscles.

  • The main functions of the titin family seem to be to interconnect myosin and actin filaments axially and provide passive elasticity; this also centres thick filaments between Z lines, so that equal forces are developed by myosin in both halves of the sarcomere. Related intracellular members of the immunoglobulin superfamily provide transverse deformable connections in the sarcomere.

Abstract

In striated muscles, the rapid production of macroscopic levels of force and displacement stems directly from highly ordered and hierarchical protein organization, with the sarcomere as the elemental contractile unit. There is now a wealth of evidence indicating that the giant elastic protein titin has important roles in controlling the structure and extensibility of vertebrate muscle sarcomeres.

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Figure 1: Electron micrographs of titin molecules.
Figure 2: Scheme for the tertiary structure of titin.
Figure 3: Force-extension relationship of single titin molecules measured by optical tweezers.
Figure 4: Scheme for tertiary structure in Z-line and M-line proteins.
Figure 5: Sarcomere structure at different degrees of extension.

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Acknowledgements

A considerable number of reports illustrating the main points of our review were not cited due to space limitations. The authors apologize to those whose work is not represented or is cited only indirectly. Research from the authors' laboratory was supported by grants from the British Heart Foundation.

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  1. Astbury Centre for Structural Molecular Biology, and School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK

    Larissa Tskhovrebova & John Trinick

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DATABASES

LocusLink

α-actinin

actin

dystrophin

filamin

MURF1

MURF2

myomesin

myosin

obscurin

telethonin

titin

unc-89

Glossary

RESTING LENGTH

The length to which the relaxed sarcomeres freely shorten in the absence of external load.

OPERATING RANGE

The length range over which sarcomeres shorten and extend in muscle in vivo.

MYOFIBRIL

The structural apparatus of striated muscle, consisting of elemental contractile units — the sarcomeres — concatenated at their boundaries, the Z-lines.

M-LINE

The transverse line at the midpoint of the sarcomere. The M-line consists of proteins that connect the thick filaments at their midpoint.

IMMUNOGLOBULIN-LIKE DOMAIN

A type of polypeptide fold that was first identified in antibodies and extracellular-matrix proteins. The domain contains ∼100 amino acids and is folded into two sandwiched β-pleated sheets of 3 or 4 strands.

Z-LINE

A region of muscle sarcomere to which the plus ends of actin filaments are attached. It appears as a dark transverse line in micrographs.

INDIRECT FLIGHT MUSCLES

High-frequency muscles that are also known as asynchronous or fibrillar muscles. In contrast to synchronous muscles, in which there is a direct correspondence between stimulus (action potential) and contractile cycle, indirect muscles can respond to an individual stimulus with a series of contractile cycles in an oscillatory fashion. In insects that use indirect muscles, the wings and thorax form a mechanically resonant system that allows muscles to oscillate with the resonant frequency.

POLYPROLINE TYPE II HELIX

A preferred conformation for proline-rich regions of protein sequences, with an axial translation of 3.20 Å and three residues in each turn of a left-handed helix. Other common polypeptide conformations are α-helix and β-structure.

SOLEUS MUSCLE

A muscle in the leg that controls postural stability. It contains one of the largest titin isoforms. This results in sarcomeres that have a comparatively long resting length and are more compliant than in other muscles. At the other end of this range is cardiac muscle, which has short, stiff sarcomeres.

OPTICAL TWEEZERS

A technique that is used for the manipulation of individual protein molecules and is based on the radiation pressure of light. A micron-sized transparent bead tends to stay at the focus of a laser beam. When the bead is attached to a protein molecule, movement of the laser beam can be used to impart small forces and displacements to the protein.

ATOMIC-FORCE SPECTROSCOPY

An imaging and force-measuring (pico/nano-Newton range) technique that is based on a sharp probing tip attached to a flexible cantilever. The probe can scan across a surface in a raster to form an image. Alternatively, the probe can pull upwards to measure forces in a molecule stretched between the probe and a surface.

RING-FINGER PROTEINS

A family of proteins that are structurally defined by the presence of the zinc-binding RING-finger motif. The RING consensus sequence is: CX2CX(9–39)CX(1–3)HX(2–3)C/HX2CX(4–48)CX2C. The cysteines and histidines represent metal binding sites. The first, second, fifth and sixth of these bind one zinc ion and the third, fourth, seventh and eighth bind the second.

TRANSVERSE (T)-TUBULES

A system of surface-connected membranes in muscle that enables a nerve impulse to travel to the interior of the muscle fibre.

SARCOLEMMA

The membrane (plasmalemma) of a muscle cell that makes an osmotic barrier around the contents of the cell.

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Tskhovrebova, L., Trinick, J. Titin: properties and family relationships. Nat Rev Mol Cell Biol 4, 679–689 (2003). https://doi.org/10.1038/nrm1198

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