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Article ; Online: Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin.

Weston, Timir G R / Rees, Martin / Gautel, Mathias / Fraternali, Franca

WIREs mechanisms of disease

2023 Volume 16, Issue 2, Page(s) e1638

Abstract: Titin, the so-called "third filament" of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of ...

Abstract	Titin, the so-called "third filament" of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well-documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants-those that result in a single amino-acid substitution in coding regions-reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin-related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well-studied giant proteins. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology.
MeSH term(s)	Humans ; Connectin/genetics ; Muscle, Skeletal/metabolism ; Muscle, Striated/physiology ; Sarcomeres/genetics
Chemical Substances	Connectin
Language	English
Publishing date	2023-12-29
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2692-9368
ISSN (online)	2692-9368
DOI	10.1002/wsbm.1638
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Book ; Thesis: Dimerisation der Gag-pol- und Pol-Polyproteine von HIV 1 und Aspekte der Pol-Prozessierung in zellfreien Transplantationssystemen

Gautel, Mathias

1990

Author's details	vorgelegt von Mathias Gautel
Size	112 Bl. : Ill., graph. Darst.
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Heidelberg, Univ., Diss., 1992
HBZ-ID	HT004002625
Database	Catalogue ZB MED Medicine, Health

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Article: Phosphorylation at Serines 157 and 161 Is Necessary for Preserving Cardiac Expression Level and Functions of Sarcomeric Z-Disc Protein Telethonin.

Lewis, Hannah R / Eminaga, Seda / Gautel, Mathias / Avkiran, Metin

Frontiers in physiology

2021 Volume 12, Page(s) 732020

Abstract: Aims: ...

Abstract	Aims:
Language	English
Publishing date	2021-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.732020
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Article ; Online: Successful heart transplant in a child with congenital core myopathy and delayed-onset restrictive cardiomyopathy due to recessive mutations in the titin (TTN) gene.

Wacker, Julie / Di Bernardo, Stefano / Lobrinus, Johannes Alexander / Jungbluth, Heinz / Gautel, Mathias / Beghetti, Maurice / Fluss, Joel

Pediatric transplantation

2023 Volume 27, Issue 6, Page(s) e14561

Abstract: Background: Mutations in the TTN gene, encoding the muscle filament titin, are a major cause of inherited dilated cardiomyopathy. Early-onset skeletal muscle disorders due to recessive TTN mutations have recently been described, sometimes associated ... ...

Abstract	Background: Mutations in the TTN gene, encoding the muscle filament titin, are a major cause of inherited dilated cardiomyopathy. Early-onset skeletal muscle disorders due to recessive TTN mutations have recently been described, sometimes associated with cardiomyopathies. Case description: We report the case of a boy with congenital core myopathy due to compound heterozygosity for TTN variants. He presented in infancy with rapidly evolving restrictive cardiomyopathy, requiring heart transplantation at the age of 5 years with favorable long-term cardiac and neuromuscular outcome. Conclusion: Heart transplantation may have a role in selected patients with TTN-related congenital myopathy with disproportionally severe cardiac presentation compared to skeletal and respiratory muscle involvement.
MeSH term(s)	Male ; Humans ; Child ; Child, Preschool ; Connectin/genetics ; Cardiomyopathy, Restrictive/complications ; Cardiomyopathy, Restrictive/genetics ; Muscular Diseases/genetics ; Mutation ; Heart Transplantation
Chemical Substances	Connectin ; TTN protein, human
Language	English
Publishing date	2023-06-22
Publishing country	Denmark
Document type	Case Reports
ZDB-ID	1390284-2
ISSN	1399-3046 ; 1397-3142
ISSN (online)	1399-3046
ISSN	1397-3142
DOI	10.1111/petr.14561
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Zs.A 4947: Show issues

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Article ; Online: The Axial Alignment of Titin on the Muscle Thick Filament Supports Its Role as a Molecular Ruler.

Bennett, Pauline / Rees, Martin / Gautel, Mathias

Journal of molecular biology

2020 Volume 432, Issue 17, Page(s) 4815–4829

Abstract: The giant protein titin is expressed in vertebrate striated muscle where it spans half a sarcomere from the Z-disc to the M-band and is essential for muscle organisation, activity and health. The C-terminal portion of titin is closely associated with the ...

Abstract	The giant protein titin is expressed in vertebrate striated muscle where it spans half a sarcomere from the Z-disc to the M-band and is essential for muscle organisation, activity and health. The C-terminal portion of titin is closely associated with the thick, myosin-containing filament and exhibits a complex pattern of immunoglobulin and fibronectin domains. This pattern reflects features of the filament organisation suggesting that it acts as a molecular ruler and template, but the exact axial disposition of the molecule has not been determined. Here, we present data that allow us to precisely locate titin domains axially along the thick filament from its tip to the edge of the bare zone. We find that the domains are regularly distributed along the filament at 4-nm intervals and we can determine the domains that associate with features of the filament, such as the 11 stripes of accessory proteins. We confirm that the nine stripes ascribed to myosin binding protein-C are not related to the titin sequence previously assumed; rather, they relate to positions approximately 18 domains further towards the C terminus along titin. This disposition also allows a subgroup of titin domains comprising two or three fibronectin domains to associate with each of the 49 levels of myosin heads in each half filament. The results strongly support the role of titin as a blueprint for the thick filament and the arrangement of the myosin motor domains.
MeSH term(s)	Animals ; Carrier Proteins/metabolism ; Connectin/chemistry ; Connectin/genetics ; Connectin/metabolism ; Mice ; Muscle, Skeletal/metabolism ; Mutation ; Protein Binding ; Protein Domains ; Protein Kinases/chemistry ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Rabbits
Chemical Substances	Carrier Proteins ; Connectin ; myosin-binding protein C ; Protein Kinases (EC 2.7.-) ; titin protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2020-07-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.06.025
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Zs.A 867: Show issues

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Article ; Online: When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability.

Fukuzawa, Atsushi / Koch, Daniel / Grover, Sarah / Rees, Martin / Gautel, Mathias

Human molecular genetics

2021 Volume 30, Issue 12, Page(s) 1131–1141

Abstract: Obscurin is a giant muscle protein that connects the sarcomere with the sarcoplasmic reticulum, and has poorly understood structural and signalling functions. Increasingly, obscurin variants are implicated in the pathophysiology of cardiovascular ... ...

Abstract	Obscurin is a giant muscle protein that connects the sarcomere with the sarcoplasmic reticulum, and has poorly understood structural and signalling functions. Increasingly, obscurin variants are implicated in the pathophysiology of cardiovascular diseases. The Arg4344Gln variant (R4344Q) in obscurin domain Ig58, initially discovered in a patient with hypertrophic cardiomyopathy, has been reported to reduce binding to titin domains Z8-Z9, impairing obscurin's Z-disc localization. An R4344Q knock-in mouse developed a cardiomyopathy-like phenotype with abnormal Ca2+-handling and arrhythmias, which were attributed to an enhanced affinity of a putative interaction between obscurin Ig58 and phospholamban (PLN) due to the R4344Q variant. However, the R4344Q variant is found in 15% of African Americans, arguing against its pathogenicity. To resolve this apparent paradox, we quantified the influence of the R4344Q variant (alongside another potentially pathogenic variant: Arg4444Trp (R4444W)) on binding to titin Z8-Z9, novex-3 and PLN using pull-down assays and microscale thermophoresis and characterized the influence on domain stability using differential scanning fluorimetry. We found no changes in titin binding and thermostability for both variants and modestly increased affinities of PLN for R4344Q and R4444W. While we could not confirm the novex-3/obscurin interaction, the PLN/obscurin interaction relies on the transmembrane region of PLN and is not reproducible in mammalian cells, suggesting it is an in vitro artefact. Without clear clinical evidence for disease involvement, we advise against classifying these obscurin variants as pathogenic.
MeSH term(s)	Animals ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/ultrastructure ; Cardiomyopathy, Hypertrophic/genetics ; Cardiomyopathy, Hypertrophic/pathology ; Connectin/genetics ; Connectin/ultrastructure ; Humans ; Mice ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscle, Skeletal/ultrastructure ; Protein Binding/genetics ; Protein Conformation ; Protein Interaction Maps/genetics ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/ultrastructure ; Protein Stability ; Rho Guanine Nucleotide Exchange Factors/genetics ; Rho Guanine Nucleotide Exchange Factors/ultrastructure ; Sarcomeres/genetics ; Sarcomeres/metabolism ; Sarcoplasmic Reticulum/genetics ; Sarcoplasmic Reticulum/metabolism ; Signal Transduction/genetics
Chemical Substances	Calcium-Binding Proteins ; Connectin ; Rho Guanine Nucleotide Exchange Factors ; phospholamban ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; obscn protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2021-01-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab010
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Zs.A 3469: Show issues

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Article ; Online: Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro.

Koch, Daniel / Kho, Ay Lin / Fukuzawa, Atsushi / Alexandrovich, Alexander / Vanaanen, Kutti J / Beavil, Andrew / Pfuhl, Mark / Rees, Martin / Gautel, Mathias

PloS one

2023 Volume 18, Issue 4, Page(s) e0284453

Abstract: Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can ... ...

Abstract	Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can activate the small GTPases RhoA and RhoQ in cells, in vitro characterization of these interactions using biophysical techniques has been hampered by the intrinsic instability of obscurin GEF domains. To study substrate specificity, mechanism and regulation of obscurin GEF function by individual domains, we successfully optimized recombinant production of obscurin GEF domains and found that MST-family kinases phosphorylate the obscurin DH domain at Thr5798. Despite extensive testing of multiple GEF domain fragments, we did not detect any nucleotide exchange activity in vitro against 9 representative small GTPases. Bioinformatic analyses show that obscurin differs from other Trio-subfamily GEFs in several important aspects. While further research is necessary to evaluate obscurin GEF activity in vivo, our results indicate that obscurin has atypical GEF domains that, if catalytically active at all, are subject to complex regulation.
MeSH term(s)	rho GTP-Binding Proteins/genetics ; Nucleotides ; Rho Guanine Nucleotide Exchange Factors/genetics ; Signal Transduction ; Muscle Proteins
Chemical Substances	rho GTP-Binding Proteins (EC 3.6.5.2) ; Nucleotides ; Rho Guanine Nucleotide Exchange Factors ; Muscle Proteins
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0284453
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Article ; Online: Cytoskeletal protein kinases: titin and its relations in mechanosensing.

Gautel, Mathias

Pflugers Archiv : European journal of physiology

2011 Volume 462, Issue 1, Page(s) 119–134

Abstract: Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca(2+) ...

Abstract	Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca(2+)-calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other "MLCKs", is not Ca(2+)-calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation.
MeSH term(s)	Amino Acid Sequence ; Animals ; Connectin ; Cytoskeletal Proteins/chemistry ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Cytoskeleton/metabolism ; Humans ; Mechanotransduction, Cellular/physiology ; Models, Molecular ; Molecular Sequence Data ; Muscle Proteins/chemistry ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Myosin-Light-Chain Kinase/chemistry ; Myosin-Light-Chain Kinase/classification ; Myosin-Light-Chain Kinase/genetics ; Myosin-Light-Chain Kinase/metabolism ; Phylogeny ; Protein Conformation ; Protein Folding ; Protein Kinases/chemistry ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Protein Unfolding ; Sequence Homology, Amino Acid
Chemical Substances	Connectin ; Cytoskeletal Proteins ; Muscle Proteins ; TTN protein, human ; Protein Kinases (EC 2.7.-) ; Myosin-Light-Chain Kinase (EC 2.7.11.18)
Language	English
Publishing date	2011-03-18
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-011-0946-1
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Article ; Online: The sarcomeric cytoskeleton: who picks up the strain?

Gautel, Mathias

Current opinion in cell biology

2010 Volume 23, Issue 1, Page(s) 39–46

Abstract: In striated muscle sarcomeres, the contractile actin and myosin filaments are organised by a subset of specialised cytoskeletal proteins, the sarcomeric cytoskeleton. They include α-actinin, myomesin, and the giant proteins titin, obscurin and nebulin, ... ...

Abstract	In striated muscle sarcomeres, the contractile actin and myosin filaments are organised by a subset of specialised cytoskeletal proteins, the sarcomeric cytoskeleton. They include α-actinin, myomesin, and the giant proteins titin, obscurin and nebulin, which combine architectural, mechanical and signalling functions. Mechanics and signalling in the sarcomere appear tightly interdependent, but the exact contributions of the various sarcomeric cytoskeleton proteins to strain handling or signalling are only just emerging. General mechanisms of cytoskeletal mechanics and signalling may be gleaned from the sarcomere as a specialised actomyosin system. Recent work has led to insight into the interactions, structure, and mechanical stability of sarcomeric protein complexes that fulfil both structural and signalling roles.
MeSH term(s)	Animals ; Cytoskeleton/metabolism ; Humans ; Sarcomeres/metabolism ; Signal Transduction
Language	English
Publishing date	2010-12-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2010.12.001
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Zs.A 2963: Show issues

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Article: The sarcomere and the nucleus: functional links to hypertrophy, atrophy and sarcopenia.

Gautel, Mathias

Advances in experimental medicine and biology

2009 Volume 642, Page(s) 176–191

Abstract: Skeletal muscle has a remarkable ability to rapidly adjust to changes in physiological requirements. This includes hypertrophic muscle growth and the atrophic loss of muscle mass, both of which occur in response to hormonal, endocrine and mechanical ... ...

Abstract	Skeletal muscle has a remarkable ability to rapidly adjust to changes in physiological requirements. This includes hypertrophic muscle growth and the atrophic loss of muscle mass, both of which occur in response to hormonal, endocrine and mechanical stimuli. In ageing muscle, sarcopenia (the loss of muscle fibres) can aggravate hormonally and mechanically induced atrophy. Hypertrophy and atrophy are associated with changes in sarcomeric protein composition and metabolic enzymes. The coordinated changes of transcriptional and splice mechanisms, protein turnover and cell fate integrates signalling pathways from hormone and cytokine receptors, as well as the sarcomere itself. This involves a number of proteins that shuttle between sarcomeric and nonsarcomeric localisations and thus convey signals from the contractile machinery to the nucleus. The M-band is emerging as a hub mainly for protein-kinase regulated ubiquitin signalling and protein turnover, whereas the I-band and Z-disk contain stretch-sensitive pathways involving transcriptional modifiers. Disruptions of these pathways can cause hereditary myopathies.
MeSH term(s)	Animals ; Atrophy/genetics ; Atrophy/metabolism ; Atrophy/pathology ; Cell Nucleus/metabolism ; Cell Nucleus/pathology ; Humans ; Hypertrophy/genetics ; Hypertrophy/metabolism ; Hypertrophy/pathology ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Muscular Diseases/genetics ; Muscular Diseases/metabolism ; Muscular Diseases/pathology ; Sarcomeres/metabolism ; Sarcomeres/pathology ; Signal Transduction
Chemical Substances	Muscle Proteins
Language	English
Publishing date	2009-01-29
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-84847-1_13
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