Association of the Chaperone αB-crystallin with Titin in Heart Muscle

Bullard, Belinda; Ferguson, Charles; Minajeva, Ave; Leake, Mark C.; Gautel, Mathias; Labeit, D.; Ding, Linlin; Labeit, Siegfried; Horwitz, Joseph; Leonard, Kevin; Linke, Wolfgang A.

doi:10.1074/jbc.m307473200

Cited by 147 publications

(149 citation statements)

References 53 publications

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“…The prototypical sHSP, aB-crystallin (22 kDa), is constitutively expressed in the eye lens and in several other tissues, notably, the cardiac and skeletal muscles and the brain 4 . In muscles, aB-crystallin binds to intermediate filaments and sarcomeric myofibrils, preventing their irreversible aggregation during stress 8,9 . It is therefore not surprising that inherited defects and the experimental gene targeting of aB-crystallin result in protein deposition diseases of cardiac and skeletal muscles 10,11 .…”

mentioning

confidence: 99%

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Pereira¹,

Santos²,

Gonçalves³

et al. 2014

Nat Commun

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Focal adhesion kinase (FAK) contributes to cellular homeostasis under stress conditions. Here we show that aB-crystallin interacts with and confers protection to FAK against calpainmediated proteolysis in cardiomyocytes. A hydrophobic patch mapped between helices 1 and 4 of the FAK FAT domain was found to bind to the b4-b8 groove of aB-crystallin. Such an interaction requires FAK tyrosine 925 and is enhanced following its phosphorylation by Src, which occurs upon FAK stimulation. aB-crystallin silencing results in calpain-dependent FAK depletion and in the increased apoptosis of cardiomyocytes in response to mechanical stress. FAK overexpression protects cardiomyocytes depleted of aB-crystallin against the stretch-induced apoptosis. Consistently, load-induced apoptosis is blunted in the hearts from cardiac-specific FAK transgenic mice transiently depleted of aB-crystallin by RNA interference. These studies define a role for aB-crystallin in controlling FAK function and cardiomyocyte survival through the prevention of calpain-mediated degradation of FAK.

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mentioning

confidence: 99%

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Pereira¹,

Santos²,

Gonçalves³

et al. 2014

Nat Commun

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“…AlphaB-crystallin directlty binds titin/connectin at the I-band region, more specifically at the N2B and I26/I27 domains, as demonstrated by both copurification and colocalization of alphaB-crystallin with titin/connectin. [24][25][26] …”

Section: Intermediate Filaments Of the Musclementioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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“…[61,62]; major histocompatibility complex formation [63,64]; T-cell maturation [65] and antigen presentation [66,67], as well as the formation of muscle sarcomeres [68,69], which includes the assembly of actin [70], desmin [71,72], myosin [73] and titin [74]. Chaperone-assisted assembly of multi-component complexes sometimes uses membrane surfaces [75][76][77] demonstrating that their attentions are not restricted to proteins, but include other biomolecules including DNA [78], RNA [79] and lipids [80][81][82].…”

Section: Assembly Chaperones: a Tried And Tested Principle Essential mentioning

confidence: 99%

“…Regulation (reg.) of the cytoskeleton is a prima facie example of the assembly chaperone role for CRYAB involving acto-myosin [70,124,125], titin [74,126] cadherin [127], tubulin [128,129] and intermediate filaments [90,130].…”

Section: The Conceptual Advance: Assembly Chaperones That Affect Bothmentioning

confidence: 99%

Chaperones: needed for both the good times and the bad times

Quinlan

Ellis

2013

Phil. Trans. R. Soc. B

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In this issue, we explore the assembly roles of protein chaperones, mainly through the portal of their associated human diseases (e.g. cardiomyopathy, cataract, neurodegeneration, cancer and neuropathy). There is a diversity to chaperone function that goes beyond the current emphasis in the scientific literature on their undoubted roles in protein folding and refolding. The focus on chaperone-mediated protein folding needs to be broadened by the original Laskey discovery that a chaperone assists the assembly of an oligomeric structure, the nucleosome, and the subsequent suggestion by Ellis that other chaperones may function in assembly processes, as well as in folding. There have been a number of recent discoveries that extend this relatively neglected aspect of chaperone biology to include proteostasis, maintenance of the cellular redox potential, genome stability, transcriptional regulation and cytoskeletal dynamics. So central are these processes that we propose that chaperones stand at the crossroads of life and death because they mediate essential functions, not only during the bad times, but also in the good times. We suggest that chaperones facilitate the success of a species, and hence the evolution of individuals within populations, because of their contributions to so many key cellular processes, of which protein folding is only one.

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Association of the Chaperone αB-crystallin with Titin in Heart Muscle

Cited by 147 publications

References 53 publications

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Intermediate Filament Diseases: Desminopathy

Chaperones: needed for both the good times and the bad times

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