Mechanoenzymatics of titin kinase

Puchner, Elias M.; Alexandrovich, Alexander; Kho, Ay Lin; Hensen, Ulf; Schäfer, Lars V.; Brandmeier, Birgit; Gräter, Frauke; Grubmüller, Helmut; Gaub, Hermann E.; Gautel, Mathias

doi:10.1073/pnas.0805034105

Cited by 311 publications

(357 citation statements)

References 38 publications

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“…The global effects exemplify "tertiary elasticity" (25,48), and contrast with "secondary structure elasticity" of other mechanosensitive molecules, e.g., titin, where straightening of linker regions between globular domains is followed by domain unraveling (reviewed in refs. 31,[49][50][51].…”

Section: Discussionmentioning

confidence: 99%

PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis

Grinthal¹,

Adamovic

Weiner³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

114

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PR65 is the two-layered (α-α solenoid) HEAT-repeat (Huntingtin, elongation factor 3, a subunit of protein phosphatase 2A, PI3 kinase target of rapamycin 1) scaffold of protein phosphatase PP2A. Molecular dynamics simulations predict that, at forces expected in living systems, PR65 undergoes (visco-)elastic deformations in response to pulling/pushing on its ends. At lower forces, smooth global flexural and torsional changes occur via even redistribution of stress along the hydrophobic core of the molecule. At intermediate forces, helix-helix separation along one layer ("fracturing") leads to global relaxation plus loss of contact in the other layer to unstack the affected units. Fracture sites are determined by unusual sequences in contiguous interhelix turns. Normal mode analysis of the heterotrimeric PP2A enzyme reveals that its ambient conformational fluctuations are dominated by elastic deformations of PR65, which introduce a mechanical linkage between the separately bound regulatory and catalytic subunits. PR65-dominated fluctuations of PP2A have the effect of opening and closing the enzyme's substrate binding/catalysis interface, as well as altering the positions of certain catalytic residues. These results suggest that substrate binding/catalysis are sensitive to mechanical force. Force could be imposed from the outside (e.g., in PP2A's response to spindle tension) or arise spontaneously (e.g., in PP2A's interaction with unstructured proteins such as Tau, a microtubule-associated Alzheimer's-implicated protein). The presented example supports the view that conformation and function of protein complexes can be modulated by mechanical energy inputs, as well as by chemical energy inputs from ligand binding. Given that helical-repeat proteins are involved in many cellular processes, the findings also encourage the view that mechanical forces may be of widespread importance.helical-repeat protein | protein elasticity | protein mechanotransduction | spindle tension

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Section: Discussionmentioning

confidence: 99%

PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis

Grinthal¹,

Adamovic

Weiner³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

114

View full text Add to dashboard Cite

show abstract

“…In so doing, titinis believed to work as a strain-sensing molecule for force adaptation in muscle. 38 Thus, embryonic organs appear to adapt their material properties in response to changes in the physical forces that occur during each developmental stage.…”

Section: Cellular Response To Ecm Stiffness During Embryonic Developmentmentioning

confidence: 99%

Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

et al. 2015

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ABSTRACT. Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression.

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“…At the M-band, the mechanically modulated kinase domain of titin interacts with a complex of the protein products of the atrogenes NBR1, p62/SQSTM1 and MuRF 73,75) . This complex dissociates under mechanical arrest, and MuRF-1 and MuRF-2 translocate to the cytoplasm and the nucleus 73,76) .…”

Section: Insulin-like Growth Factor-i and Mapk (Proliferation Phase)mentioning

confidence: 99%

Recent research developments in regeneration of skeletal muscle

Sakuma

Yamaguchi

2012

JPFSM

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Over the last decade, extensive progress has been made with regard to our understanding of the molecules that regulate skeletal muscle regeneration. Satellite cells are musclespecific stem cells located under the basal lamina of muscle fibers, which are responsible for muscle regeneration. This precise coordination of complex stem cell responses throughout adult life is regulated by evolutionarily conserved signaling networks that cooperatively direct and control. This process includes the activation, proliferation, and differentiation of stem cells. This highly regulated process of tissue regeneration recapitulates embryonic organogenesis with respect to the involvement of interactive signal transduction networks. Indeed, various modulators such as insulin-like growth factor-I (IGF-I), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) have been shown to stimulate the activation and proliferation of satellite cells. PI3K (phosphatidylinositol 3-kinase)/Akt/mTOR (mammalian target of rapamycin), calcineurin, and serum response factor (SRF) seem to contribute to muscle regeneration by regulating differentiation of satellite cells. In contrast, myostatin inhibits these processes through forkhead box O (FOXO) and/or SMAD 2/3-dependent signaling. In this review, the recent findings for muscle regeneration are described.

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Mechanoenzymatics of titin kinase

Cited by 311 publications

References 38 publications

PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis

PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis

Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

Recent research developments in regeneration of skeletal muscle

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