Restoring force development by titin/connectin and assessment of Ig domain unfolding

Nair, Preetha; Wu, Yingliang; Helmes, Michiel; Fukuda, Norio; Labeit, Siegfried; Granzier, Henk

doi:10.1007/s10974-005-9037-2

Cited by 27 publications

(17 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the strained state, as in vivo , force is applied to the termini of I27 in opposing direction. It remains controversial if IG domains in muscle titin ever fully unfold under physiological forces [26]–[28]. We here are interested in the force propagation within the fully folded protein, the physiologically relevant force-bearing structure.…”

Section: Resultsmentioning

confidence: 99%

Mechanical Network in Titin Immunoglobulin from Force Distribution Analysis

Stacklies¹,

Vega

Wilmanns³

et al. 2009

PLoS Comput Biol

View full text Add to dashboard Cite

The role of mechanical force in cellular processes is increasingly revealed by single molecule experiments and simulations of force-induced transitions in proteins. How the applied force propagates within proteins determines their mechanical behavior yet remains largely unknown. We present a new method based on molecular dynamics simulations to disclose the distribution of strain in protein structures, here for the newly determined high-resolution crystal structure of I27, a titin immunoglobulin (IG) domain. We obtain a sparse, spatially connected, and highly anisotropic mechanical network. This allows us to detect load-bearing motifs composed of interstrand hydrogen bonds and hydrophobic core interactions, including parts distal to the site to which force was applied. The role of the force distribution pattern for mechanical stability is tested by in silico unfolding of I27 mutants. We then compare the observed force pattern to the sparse network of coevolved residues found in this family. We find a remarkable overlap, suggesting the force distribution to reflect constraints for the evolutionary design of mechanical resistance in the IG family. The force distribution analysis provides a molecular interpretation of coevolution and opens the road to the study of the mechanism of signal propagation in proteins in general.

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanical Network in Titin Immunoglobulin from Force Distribution Analysis

Stacklies¹,

Vega

Wilmanns³

et al. 2009

PLoS Comput Biol

View full text Add to dashboard Cite

show abstract

“…Dissociated fibers attach to the laminin substrate without any constraint at their slack length, which is set in the first place by myofibrillar proteins such as titin [28–30]. There are, however, no reasons to believe that the shorter sarcomere length observed in Col6a1−/− and mdx fibers is an indication of a difference in myofibrillar proteins.…”

Section: Discussionmentioning

confidence: 99%

Mechanical and Electrophysiological Properties of the Sarcolemma of Muscle Fibers in Two Murine Models of Muscle Dystrophy: Col6a1−/−and Mdx

Canato

Maschio

Sbrana

et al. 2010

Journal of Biomedicine and Biotechnology

View full text Add to dashboard Cite

This study aimed to analyse the sarcolemma of Col6a1−/− fibers in comparison with wild type and mdx fibers, taken as positive control in view of the known structural and functional alterations of their membranes. Structural and mechanical properties were studied in single muscle fibers prepared from FDB muscle using atomic force microscopy (AFM) and conventional electrophysiological techniques to measure ionic conductance and capacitance. While the sarcolemma topography was preserved in both types of dystrophic fibers, membrane elasticity was significantly reduced in Col6a1−/− and increased in mdx fibers. In the membrane of Col6a1−/− fibers ionic conductance was increased likely due to an increased leakage, whereas capacitance was reduced, and the action potential (ap) depolarization rate was reduced. The picture emerging from experiments on fibers in culture was consistent with that obtained on intact freshly dissected muscle. Mdx fibers in culture showed a reduction of both membrane conductance and capacitance. In contrast, in mdx intact FDB muscle resting conductance was increased while resting potential and ap depolarization rate were reduced, likely indicating the presence of a consistent population of severely altered fibers which disappear during the culture preparation.

show abstract

“…Moreover, elastic recoil of the stretched titin spring could support active muscle shortening, although viscous drag forces largely arising from titin-thin filament interactions (like those involving the PEVK region (60)) put a brake on titin recoil speed (61). In cardiac sarcomeres shortened to below slack length, the titin springs are a source of restoring forces, which bring the sarcomere (and the myocardium in early diastole) back to its resting length ("diastolic suction") (62). Finally, titin is suggested to be involved in determining the length-dependent activation of cardiac muscle (63)(64)(65), which is the basis for the increase in work output with increased diastolic filling, also known as the Frank-Starling mechanism of the heart.…”

Section: Mechanical Functions Of Titinmentioning

confidence: 99%

The Giant Protein Titin: A Regulatory Node That Integrates Myocyte Signaling Pathways

Krüger

Linke

2011

Journal of Biological Chemistry

148

125

View full text Add to dashboard Cite

Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control.The specialized cytoskeleton of striated muscle cells consists of highly ordered structures, the sarcomeres, which are built of myosin, actin, and titin filaments (Fig. 1), along with a plethora of other structural and regulatory proteins. The cytoskeleton is no longer seen as a static skeleton that fixes each cellular component but as a dynamic and sensitive cellular organizer that responds to various extracellular clues. Muscle cells are no exception to this; however, some responses to external signals are unique to myocytes due to the specialized protein composition and ordered arrangement of the sarcomeres. In this minireview, we first provide general information on the structure and function of the giant muscle protein titin (also known as connectin) and then focus on the dynamic role of titin as an important regulatory node in the sarcomeric cytoskeleton. Special attention is paid to emerging evidence suggesting that phosphorylation by various protein kinases alters titin function.

show abstract

Restoring force development by titin/connectin and assessment of Ig domain unfolding

Cited by 27 publications

References 47 publications

Mechanical Network in Titin Immunoglobulin from Force Distribution Analysis

Mechanical Network in Titin Immunoglobulin from Force Distribution Analysis

Mechanical and Electrophysiological Properties of the Sarcolemma of Muscle Fibers in Two Murine Models of Muscle Dystrophy: Col6a1−/−and Mdx

The Giant Protein Titin: A Regulatory Node That Integrates Myocyte Signaling Pathways

Contact Info

Product

Resources

About