Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Sarparanta, J.; Blandin, Gaëlle; Charton, Karine; Vihola, Anna; Marchand, Sylvie; Milić, Astrid; Hackman, Peter; Ehler, Elisabeth; Richard, Isabelle; Udd, Bjarne

doi:10.1074/jbc.m110.108720

Cited by 61 publications

(62 citation statements)

References 47 publications

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“…5). The interaction of titin with several ubiquitin ligases (the complex of MURF1/2/3 near the kinase domain; Centner et al, 2001), and myospryn at M10 (Sarparanta et al, 2010), as well as ubiquitinbinding autophagy adaptor proteins (Nbr1 and p62/SQSTM1; Lange et al, 2005b) suggests that titin is either a substrate or a regulator of these pathways. Whether these activities require titin kinase activity or solely its scaffolding role remains to be clarified (Bogomolovas et al, 2014;Lange et al, 2005b).…”

Section: M-band Cytoskeleton: All's Well That Ends Wellmentioning

confidence: 99%

“…Titin interacts additionally with the cysteine protease calpain-3 in the differentially spliced insertion between domains M9 and M10 (Kinbara et al, 1997); this interaction seems to be dynamically modulated by mechanical forces (Ojima et al, 2010). Interestingly, calpain-3 interacts in turn with myospryn, linking the activity of the two pathways in protein degradation (Sarparanta et al, 2010); the generation of C-terminal titin fragments by calpain might be the prelude to their ubiquitin-dependent degradation, a process that is disrupted in several hereditary titinopathies (Charton et al, 2015;Sarparanta et al, 2010).…”

Section: M-band Cytoskeleton: All's Well That Ends Wellmentioning

confidence: 99%

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The sarcomeric cytoskeleton: from molecules to motion

Gautel

Djinović-Carugo

2016

Journal of Experimental Biology

190

184

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Highly ordered organisation of striated muscle is the prerequisite for the fast and unidirectional development of force and motion during heart and skeletal muscle contraction. A group of proteins, summarised as the sarcomeric cytoskeleton, is essential for the ordered assembly of actin and myosin filaments into sarcomeres, by combining architectural, mechanical and signalling functions. This review discusses recent cell biological, biophysical and structural insight into the regulated assembly of sarcomeric cytoskeleton proteins and their roles in dissipating mechanical forces in order to maintain sarcomere integrity during passive extension and active contraction. α-Actinin crosslinks in the Z-disk show a pivot-and-rod structure that anchors both titin and actin filaments. In contrast, the myosin crosslinks formed by myomesin in the M-band are of a balland-spring type and may be crucial in providing stable yet elastic connections during active contractions, especially eccentric exercise.

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Section: M-band Cytoskeleton: All's Well That Ends Wellmentioning

confidence: 99%

Section: M-band Cytoskeleton: All's Well That Ends Wellmentioning

confidence: 99%

The sarcomeric cytoskeleton: from molecules to motion

Gautel

Djinović-Carugo

2016

Journal of Experimental Biology

190

184

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“…76 Two ligands of the last Ig-domain in titin (Ig152) are myospryn and obscurin/obscurin-like 1, both of which have structural and signaling functions. [77][78][79] Obscurin and myospryn have also been observed at the Z-disk, raising the possibility that these proteins shuttle between 2 sarcomeric hubs depending on developmental stage or disease condition.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

286

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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“…This 449 kDa heavy protein with the official gene name CMYA5 (cardiomyopathyassociated 5) was identified by expression profiling of a cardiac muscle library and has since been found to interact specifically with PKA-RIIα but not (or hardly) with the other PKA-R isoforms (Reynolds et al, 2007). Intriguingly, endogenous myospryn localization in the sarcomere exhibited the expected m-and z-line expression pattern fitting to PKA-RIIα distribution (Reynolds et al, 2007) while in another study myospryn showed only faint m-line and strong I-band distribution (Sarparanta et al, 2010). Whether this could indicate natural variability or be due to other factors is unclear, but myospryn is now widely considered to be an important determinant for PKA microdomain formation in skeletal and heart muscle.…”

Section: Pka Microdomains At the Sarcomeric Regionmentioning

confidence: 93%

“…Whether this could indicate natural variability or be due to other factors is unclear, but myospryn is now widely considered to be an important determinant for PKA microdomain formation in skeletal and heart muscle. In the recent past, more and more proteins were found to interact with myospryn, including the structural proteins α-actinin (Durham et al, 2006), desmin (Kouloumenta et al, 2007), dystrophin , and titin (Sarparanta et al, 2010), as well as proteolytic enzymes such as the muscle-specific protease, calpain 3 (Sarparanta et al, 2010), and the protein phosphatase calcineurin (Kielbasa et al, 2011). Notably, these proteins all play important roles in muscle integrity and metabolic adaptations suggesting a mediator role of myospryn in these processes (Sarparanta, 2008).…”

Section: Pka Microdomains At the Sarcomeric Regionmentioning

confidence: 99%

Interação funcional entre o sistema colinérgico e adrenérgico na manutenção da massa muscular e da placa motora

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Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies

Cited by 61 publications

References 47 publications

The sarcomeric cytoskeleton: from molecules to motion

The sarcomeric cytoskeleton: from molecules to motion

Gigantic Business

Interação funcional entre o sistema colinérgico e adrenérgico na manutenção da massa muscular e da placa motora

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