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J. Cell Biol.,
Volume 140, Number 4, February 23, 1998 853-859
* Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman,
Washington 99164-6520; Abstract. Titin (also known as connectin) is a giant
protein that spans half of the striated muscle sarcomere. In the I-band titin extends as the sarcomere is
stretched, developing what is known as passive force.
The I-band region of titin contains tandem Ig segments
(consisting of serially linked immunoglobulin-like domains) with the unique PEVK segment in between (Labeit, S., and B. Kolmerer. 1995. Science. 270:293-296).
Although the tandem Ig and PEVK segments have
been proposed to behave as stiff and compliant springs,
respectively, precise experimental testing of the hypothesis is still needed. Here, sequence-specific antibodies were used to mark the ends of the tandem Ig
and PEVK segments. By following the extension of the
segments as a function of sarcomere length (SL), their
respective contributions to titin's elastic behavior were
established. In slack sarcomeres (~2.0 µm) the tandem Ig and PEVK segments were contracted. Upon stretching sarcomeres from ~2.0 to 2.7 µm, the "contracted"
tandem Ig segments straightened while their individual
Ig domains remained folded. When sarcomeres were
stretched beyond ~2.7 µm, the tandem Ig segments did
not further extend, instead PEVK extension was now
dominant. Modeling tandem Ig and PEVK segments as
entropic springs with different bending rigidities
(Kellermayer, M., S. Smith, H. Granzier, and C. Bustamante. 1997. Science. 276:1112-1116) indicated that in the physiological SL range (a) the Ig-like domains of
the tandem Ig segments remain folded and (b) the
PEVK segment behaves as a permanently unfolded
polypeptide. Our model provides a molecular basis for
the sequential extension of titin's different segments. Initially, the tandem Ig segments extend at low forces
due to their high bending rigidity. Subsequently, extension of the PEVK segment occurs only upon reaching
sufficiently high external forces due to its low bending
rigidity. The serial linking of tandem Ig and PEVK segments with different bending rigidities provides a
unique passive force-SL relation that is not achievable
with a single elastic segment.
Muscle Biology Laboratory, University of Wisconsin, Madison, Wisconsin 53706-1181; § European
Molecular Biology Laboratory, 69012 Heidelberg, Germany; and Department of Physiology and Biophysics, Case Western
Reserve University, Cleveland, Ohio 44106-4970
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