Different Molecular Mechanics Displayed by Titin's Constitutively and Differentially Expressed Tandem Ig Segments

Watanabe, Kaori; Muhle‐Goll, Claudia; Kellermayer, Miklós; Labeit, Siegfried; Granzier, Henk

doi:10.1006/jsbi.2002.4458

Cited by 78 publications

(75 citation statements)

References 39 publications

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“…It is noteworthy that the 32.8 nm average contour length gain per unfolding event in Ig24 is 2.1 nm larger than that of Ig domains in Ig 1-15 ( Fig. 6B, inset) and 4.5 nm larger than previously measured for the Ig 91-98 domains (18). Some differences in CL gain can be expected due to the different number of residues contained in the Ig domains of titin (18,27).…”

Section: Discussionmentioning

confidence: 59%

“…6B, inset) and 4.5 nm larger than previously measured for the Ig 91-98 domains (18). Some differences in CL gain can be expected due to the different number of residues contained in the Ig domains of titin (18,27). It is unlikely, however, that the large CL gain of the Ig 24 -26 domain can be explained this way, because the domains have an average of 85 residues (predicted by the sequence of Ref.…”

Section: Discussionmentioning

confidence: 71%

“…It is unlikely, however, that the large CL gain of the Ig 24 -26 domain can be explained this way, because the domains have an average of 85 residues (predicted by the sequence of Ref. 11 and using SMART (Simple Modular Architecture Research Tool) on the World Wide Web), which is less than the 92 residues on average contained in the Ig 1-15 and 89 residues in Ig 91-98 (18,27). The contour length gain upon unfolding can be calculated from the number of residues in the domain times 0.38 nm/residue minus the size of a folded domain (5.3 nm; see "Results").…”

Section: Discussionmentioning

confidence: 99%

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Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Zhu

Bogomolovas

Labeit

et al. 2009

Journal of Biological Chemistry

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The small heat shock protein ␣B-crystallin interacts with N2B-Us, a large unique sequence found in the N2B element of cardiac titin. Using single molecule force spectroscopy, we studied the effect of ␣B-crystallin on the N2B-Us and its flanking Ig-like domains. Ig domains from the proximal tandem Ig segment of titin were also studied. The effect of wild type ␣B-crystallin on the single molecule force-extension curve was determined as well as that of mutant ␣B-crystallins harboring the dilated cardiomyopathy missense mutation, R157H, or the desmin-related myopathy mutation, R120G. Results revealed that wild type ␣B-crystallin decreased the persistence length of the N2B-Us (from ϳ0.7 to ϳ0.2 nm) but did not alter its contour length. ␣B-crystallin also increased the unfolding force of the Ig domains that flank the N2B-Us (by 51 ؎ 3 piconewtons); the rate constant of unfolding at zero force was estimated to be ϳ17-fold lower in the presence of ␣B-crystallin (1.4 ؋ 10 ؊4 s ؊1 versus 2.4 ؋ 10 ؊3 s ؊1 ). We also found that ␣B-crystallin increased the unfolding force of Ig domains from the proximal tandem Ig segment by 28 ؎ 6 piconewtons. The effects of ␣B-crystallin were attenuated by the R157H mutation (but were still significant) and were absent when using the R120G mutant. We conclude that ␣B-crystallin protects titin from damage by lowering the persistence length of the N2B-Us and reducing the Ig domain unfolding probability. Our finding that this effect is either attenuated (R157H) or lost (R120G) in disease causing ␣B-crystallin mutations suggests that the interaction between ␣B-crystallin and titin is important for normal heart function.␣B-crystallin is a member of the small heat shock protein family that by inhibiting denaturation and aggregation of proteins functions as a molecular chaperone (1). Although ␣B-crystallin has been most intensively studied in the vertebrate eye lens, it is also found in many other tissues (2) with cardiac muscle expressing ␣B-crystallin at 3-5% of the total soluble protein (3). Up-regulation of ␣B-crystallin occurs in a number of cardiac disorders, including familial cardiac hypertrophy, and overexpression appears to protect the cardiac cell from ischemia reperfusion injury (for a review see Ref. 4). An important binding partner of ␣B-crystallin in cardiac muscle is titin (5, 6). Titin is a large filamentous protein that forms a continuous filament along the myofibril, with single titin molecules spanning from the edge to the middle of the sarcomere, a distance of ϳ1 m (7). The I-band region of titin is extensible and functions as a molecular spring that, when extended, develops force (8, 9). This force is an important determinant of the passive stiffness of the heart that determines the filling characteristics during the diastolic part of the heart cycle (10). The interaction between ␣B-crystallin and titin could be important for maintaining heart function, especially when stressed, such as during ischemia (5), warranting studies of the effect of ␣B-crystallin on the biomechanica...

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Zhu

Bogomolovas

Labeit

et al. 2009

Journal of Biological Chemistry

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“…Adjacent to the Z-line, the constitutive proximal Ig segment contains most of the weak Ig domains, with average unfolding forces of ϳ150 pN (36,44). The differentially expressed domains, which are centrally positioned in the I-band, have intermediate stability and unfolding forces of ϳ200 pN (43,45). Near the I/A junction, the constitutive distal segment contains the strongest domains, with an unfolding force of ϳ250 pN (43)(44)(45).…”

Section: Minireview: Properties Of Titin Ig and Fn3 Domains 46352mentioning

confidence: 99%

“…The differentially expressed domains, which are centrally positioned in the I-band, have intermediate stability and unfolding forces of ϳ200 pN (43,45). Near the I/A junction, the constitutive distal segment contains the strongest domains, with an unfolding force of ϳ250 pN (43)(44)(45). Finally, the average unfolding rate constant of the proximal Ig domains is higher (ϳ10 Ϫ3 s Ϫ1 ) than that of the distal Ig domains (ϳ10 Ϫ4 s…”

Section: Minireview: Properties Of Titin Ig and Fn3 Domains 46352mentioning

confidence: 99%

Properties of Titin Immunoglobulin and Fibronectin-3 Domains

Tskhovrebova

Trinick

2004

Journal of Biological Chemistry

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Structure–function relations of the giant elastic protein titin in striated and smooth muscle cells

2007

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The striated muscle sarcomere contains, in addition to thin and thick filaments, a third myofilament comprised of titin. The extensible region of titin spans the I-band region of the sarcomere and develops passive force in stretched sarcomeres. This force positions the A-bands in the middle of the sarcomere, maintains sarcomere length homogeneity and, importantly, is responsible for myocardial passive tension that determines diastolic filling. Recent work suggests that smooth muscle expresses a truncated titin isoform with a short extensible region that is predicted to develop high passive force levels. Several mechanisms for tuning the titin-based passive tension have been discovered that involve alternative splicing as well as posttranslational modification, mechanisms that are at play both during normal muscle function as well as during disease.

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Different Molecular Mechanics Displayed by Titin's Constitutively and Differentially Expressed Tandem Ig Segments

Cited by 78 publications

References 39 publications

Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Properties of Titin Immunoglobulin and Fibronectin-3 Domains

Structure–function relations of the giant elastic protein titin in striated and smooth muscle cells

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