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© The Rockefeller University Press, 0021-9525/1998//853 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 853-859

Article

Titin Extensibility In Situ: Entropic Elasticity of Permanently Folded and Permanently Unfolded Molecular Segments



Karoly Trombitás*, Marion Greaser{ddagger}, Siegfried Labeit§, Jian-Ping Jin||, Miklós Kellermayer*, Michiel Helmes*, and Henk Granzier*

* Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164-6520; {ddagger} 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

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.

1. Abbreviations used in this paper: SL, sarcomere length; WLC, wormlike chain.

We are grateful to Dr. G. French for his help in obtaining muscle biopsies and to Dr. Gyöngyi Kellermayer and Mark McNabb for their excellent technical assistance.

This work was supported by grants from the National Institutes of Health (HL-47053 to M. Greaser and AR-42652 to H. Granzier) and Deutshce Forschungsgemeinschaft, La668/2-3 to S. Labeit. H. Granzier is an Established Investigator of the American Heart Association.

Address correspondence and reprint requests to Henk Granzier, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99164-6520. Tel.: (509) 335-3390. FAX: (509) 335-4650. E-mail: granzier{at}wsunix.wsu.edu

Dr. Kellermayer's present address is Central Laboratory, University Medical School of Pécs, Pécs, H-7626, Hungary.


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