Towards a molecular understanding of titin.

Labeit, Siegfried; Gautel, Mathias; Lakey, Anne F.; Trinick, John

doi:10.1002/j.1460-2075.1992.tb05222.x

Cited by 331 publications

(267 citation statements)

References 39 publications

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“…The fibronectin domains of titin are found almost exclusively in the predicted A-band region of the molecule (Labeit and Kolnierer, 1995) and are therefore likely to be specific for the interaction of titin with myosin. This view is supported by the finding that the binding affinity of recombinant multi-module fragments of titin to myosin increases with the number 0 1 fibronectin domains (Labeit et al, 1992). In contrast, Ig-I domains are found over the entire extent of the titin molecule (Labeit and Kolmerer, 1995), suggesting that they inay be responsible for the interaction of titin with ligands other than myosin.…”

Section: Discussionmentioning

confidence: 91%

“…Firstly, they are found in distinct patterns (super-repeats; Labeit et al, 1992) along the molecule that appear to correlate to the ultrastructural spacing of the 11 transverse thick-filament stripes, which are caused by the local protein density of the myosin-binding proteins. This view is strongly supported by the complete sequence of titin in the Aband which reveals the presence of 11 11 -domain super-repeats.…”

Section: Discussionmentioning

confidence: 99%

“…This specific assembly is directed by the association to myosin filaments, which is mediated by a C-terminal myosin-binding Tg-I domain conserved within the whole family (Okagaki et al, 1993). MyBP-C also binds to recombinant Aband fragments of titin (Labeit et al, 1992) as well as to native titin (Furst et al, 1992;Soteriou et al, 1993), and it was thereumed that its subsarcomeric distribution was specified by this interaction (Furst et al, 1989(Furst et al, , 1992Labeit and Kolmerer, 1995). The A-band sequence of titin was previously shown to consist of regular arrays of fn-3 and Ig-I modules, arranged in super-repeats of 11 domains (Labeit et al, 1992) with an expected dimension of approximately 43 nm.…”

mentioning

confidence: 99%

“…MyBP-C also binds to recombinant Aband fragments of titin (Labeit et al, 1992) as well as to native titin (Furst et al, 1992;Soteriou et al, 1993), and it was thereumed that its subsarcomeric distribution was specified by this interaction (Furst et al, 1989(Furst et al, , 1992Labeit and Kolmerer, 1995). The A-band sequence of titin was previously shown to consist of regular arrays of fn-3 and Ig-I modules, arranged in super-repeats of 11 domains (Labeit et al, 1992) with an expected dimension of approximately 43 nm. The complete sequence of A-band titin now reveals the presence of l l copies of the 1 1-domain super-repeats (numbererd 1 -11 from N-terminus to C-terminus).…”

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confidence: 99%

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A Molecular Map of the Interactions between Titin and Myosin‐Binding Protein C

Freiburg

Gautel

1996

European Journal of Biochemistry

260

209

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The thick filaments of vertebrate striated muscles contain with myosin a number of accessory proteins of the intracellular immunoglobulin superfamily, which are localized in a distinct pattern of stripes 43 nm apart. The specific localization of these proteins is believed to be due partly to their interaction with the giant muscle protein titin (also called connectin), which spans the entire sarcomere and may act as a molecular ruler. We have used recombinant fragments of titin covering the thick filament region to investigate their interaction with myosin-binding protein C (MyBP-C) from skeletal and cardiac muscle. The interaction of titin and MyBP-C is directed by a subset of titin immunoglobulin domains that are specific for the C-region of the thick filament, supporting the ruler hypothesis for the myosin-binding proteins. The interaction of recombinant titin with overlapping fragments of human cardiac MyBP-C maps the titinbinding site within the C-terminal region, which is deleted in patients suffering from the chromosome-1 1-associated form of familial hypertrophic cardiomyopathy. This disorder is therefore likely to be the result of thick-filament misassembly by abolishing the ternary interaction of titin, inyosin and MyBP-C.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Molecular Map of the Interactions between Titin and Myosin‐Binding Protein C

Freiburg

Gautel

1996

European Journal of Biochemistry

260

209

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“…At the M-band, titin contains a serine/ threonine protein kinase domain (TK) (Fig. 1B) (3,4). TK is regulated in a dual autoinhibition mechanism by a C-terminal regulatory tail, blocking the ATP binding site, and tyrosine autoinhibition of the catalytic base by tyrosine-170 (5).…”

mentioning

confidence: 99%

Mechanoenzymatics of titin kinase

Puchner

Alexandrovich

Kho

et al. 2008

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

313

332

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Biological responses to mechanical stress require strain-sensing molecules, whose mechanically induced conformational changes are relayed to signaling cascades mediating changes in cell and tissue properties. In vertebrate muscle, the giant elastic protein titin is involved in strain sensing via its C-terminal kinase domain (TK) at the sarcomeric M-band and contributes to the adaptation of muscle in response to changes in mechanical strain. TK is regulated in a unique dual autoinhibition mechanism by a C-terminal regulatory tail, blocking the ATP binding site, and tyrosine autoinhibition of the catalytic base. For access to the ATP binding site and phosphorylation of the autoinhibitory tyrosine, the C-terminal autoinhibitory tail needs to be removed. Here, we use AFM-based single-molecule force spectroscopy, molecular dynamics simulations, and enzymatics to study the conformational changes during strain-induced activation of human TK. We show that mechanical strain activates ATP binding before unfolding of the structural titin domains, and that TK can thus act as a biological force sensor. Furthermore, we identify the steps in which the autoinhibition of TK is mechanically relieved at low forces, leading to binding of the cosubstrate ATP and priming the enzyme for subsequent autophosphorylation and substrate turnover.

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Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals

et al. 2021

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IMPORTANCEAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.OBJECTIVES To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTSIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged Յ66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes.

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Towards a molecular understanding of titin.

Cited by 331 publications

References 39 publications

A Molecular Map of the Interactions between Titin and Myosin‐Binding Protein C

A Molecular Map of the Interactions between Titin and Myosin‐Binding Protein C

Mechanoenzymatics of titin kinase

Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals

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