Prof. Mathias Gautel

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Academic Career Length

37Years (1990-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

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16 May 1997 in Science

Journal Article

Reversible Unfolding of Individual Titin Immunoglobulin Domains by AFM

Matthias Rief

Mathias Gautel

Filipp Oesterhelt

Julio M. Fernandez

Hermann E. Gaub

Single-molecule atomic force microscopy (AFM) was used to investigate the mechanical properties of titin, the giant sarcomeric protein of striated muscle. Individual titin molecules were repeatedly stretched, and the applied force was recorded as a function of the elongation. At large extensions, the restoring force exhibited a sawtoothlike pattern, with a periodicity that varied between 25 and 28 nanometers. Measurements of recombinant titin immunoglobulin segments of two different lengths exhibited the same pattern and allowed attribution of the discontinuities to the unfolding of individual immunoglobulin domains. The forces required to unfold individual domains ranged from 150 to 300 piconewtons and depended on the pulling speed. Upon relaxation, refolding of immunoglobulin domains was observed.

23 May 2011 in Nature Reviews Molecular Cell Biology

Journal Article

Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis

Thomas Braun

Mathias Gautel

10 June 2005 in Science

Journal Article

The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

Stephan Lange

Fengqing Xiang

Andrey Yakovenko

Anna Vihola

Peter Hackman

Mathias Gautel

+13

The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.

1 December 1995 in Nature Genetics

Journal Article

Cardiac myosin binding protein–C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy

Gisèle Bonne

Lucie Carrier

Josiane Bercovici

Corinne Cruaud

Pascale Richard

Ketty Schwartz

29 October 1998 in Nature

Journal Article

Structural basis for activation of the titin kinase domain during myofibrillogenesis

Mayans Olga

Peter F. M. van der Ven

Matthias Wilm

A Mues

Paul Young

Mathias Gautel

9 September 2008 in Proceedings of the National Academy of Sciences

Journal Article

Mechanoenzymatics of titin kinase

Elias M. Puchner

Alexander Alexandrovich

Ay Lin Kho

Ulf Hensen

Lars V. Schäfer

Mathias Gautel

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.

About Me

Prof. Dr. Mathias Gautel is the BHF Professor of Molecular Cardiology at King’s College London, whose research is focused on the contractile structures of heart and skeletal muscles at the atomic and cellular levels to understand the mechanisms of inherited muscle diseases. He obtained his MD from Heidelberg University in 1991. He was then a post-doctoral fellow and visiting team leader (1996–1998) at EMBL Heidelberg, where he worked on his habilitation (MD PhD equivalent) in Biochemistry on titin-based sarcomere assembly at Heidelberg University in 1998. After nine years at EMBL, he was awarded a Heisenberg Fellowship by the German Research Foundation and joined the Max Planck Institute of Molecular Physiology, Dortmund, as a group leader. He was appointed as Professor of Molecular Cardiology at King’s College London in 2002, and since 2008, he has held the British Heart Foundation Chair of Molecular Cardiology. He is the Head of the School of Basic and Medical Biosciences at KCL. His research has been supported by UK research councils (MRC, BBSRC), as well as the British Heart Foundation, Wellcome Trust, Leducq Foundation, Volkswagen Foundation, the EU and the European Research Council, and the German Research Foundation DFG. He was awarded the International Society for Heart Research (ISHR) Outstanding Investigator Award in 2009 and was elected as a Fellow of the Academy of Medical Sciences (FMedSci) in 2010.

Prof. Mathias Gautel

Prof. Mathias Gautel

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