Impact of MFM disease mutations on the assembly mechanism and network formation of muscle-specific intermediate filament proteins

• Applicant: Professor Dr. Harald Herrmann
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2009 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101925924

• Final Report Year: 2017

Final Report Abstract

We have demonstrated the impact of point mutations in desmin on the assembly of the protein into filament networks and their interaction with large authentic structural muscle proteins such as nebulin and nebulette. Furthermore, we investigated the interaction of desmin with the IF proteins synemin-L and nestin identifying both proteins not to be authentic IF proteins, expected to form hetero-dimeric or hetero-tetrameric complexes with desmin. Instead, according to our results, these proteins should be classified as IF-associated proteins what may have important implications with respect to how we look at their incorporation into the differentiating muscle cell. Moreover, we investigated the interaction of both wild-type and mutated desmins with the small heat shock protein αB-crystallin/HSPB5. From these experiments it is clear that the chaperone does not only help to assemble unit-length filaments but also exhibits a sensor function during assembly, discriminating between wild-typ desmin filaments and filaments formed by mutated desmins. Accordingly, these results may explain why mutations in αB-crystallin/HSPB5 can lead to a complete reorganization of the desmin network in patient myocytes.

Publications

• Nebulin binding impedes mutant desmin filament assembly. Mol Biol Cell 2013; 24:1918-1932
  Baker LK, Gillis DC, Sharma S, Ambrus A, Herrmann H, Conover GM
  
• Attractive interactions among intermediate filaments determine network mechanics in vitro. PLoS One 2014; 9:e93194
  Pawelzyk P, Mücke N, Herrmann H, Willenbacher N
  
• Impact of ion valency on the assembly of vimentin studied by quantitative small angle X-ray scattering. Soft Matter 2014; 10: 2059-68
  Brennich M, Bauch S, Vainio U, Wedig T, Herrmann H, Köster S
  
• Mechanosensing through focal adhesion-anchored intermediate filaments. FASEB J 2014; 28:715-729
  Gregor M, Osmanagic-Myers S, Burgstaller G, Wolfram M, Fischer I, Walko G, Resch GP, Jörgl A, Herrmann H, Wiche G
  
• Microtubule-dependent transport of vimentin filament precursors is regulated by actin and the concerted action of Rho- and p21-activated kinases. FASEB J 2014; 28:2879-2890
  Robert A, Herrmann H, Davidson MW, Gelfand VI
  
• Sequenceresolved free energy profiles of stress-bearing vimentin intermediate filaments. Proc Natl Acad Sci USA 2014; 111:11359-11364
  Ramm B, Stigler J, Hinczewski M, Thirumalai D, Herrmann H, Woehlke G, Rief M
  
• The toxic effect of R350P mutant desmin in striated muscle of man and mouse. Acta Neuropathol 2015; 129:297-315
  Clemen CS, Stöckigt F, Strucksberg KH, Chevessier F, Winter L, Schütz J, Bauer R, Thorweihe JM, Wenzel D, Schneider-Stock R, Schlötzer-Schrehardt U, Rasche V, Krsmanovic P, Katus HA, Rottbauer W, Just S, Müller O, Friedrich O, Meyer R, Herrmann H, Schrickel JW, Schröder R
  
• In vitro Assembly Kinetics of Cytoplasmic Intermediate Filaments: A Correlative Monte Carlo Simulation Study. PLoS One 2016; 11:e0157451
  Mücke N, Winhein S, Merlitz H, Buchholz J, Langowski J, Herrmann H
  
• Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts. Mol Biol Cell 2016; 27:3869-3882
  Hernandez DA, Bennett CM, Dunina-Barkovskaya L, Wedig T, Capetanaki Y, Herrmann H, Conover G
  
• Structural Dynamics of the Vimentin Coiled-Coil Contact Regions involved in Filament Assembly as revealed by Hydrogen-Deuterium Exchange. J Biol Chem 2016; 291:24931–24950
  Premchandar A, Mücke N, Poznański J, Wedig T, Kaus-Drobek M, Herrmann H, Dadlez M
  
• The filament forming reactions of vimentin tetramers studied in a serial-inlet microflow device by small angle x-ray scattering. Biomicrofluidics 2016; 10:024108
  Saldanha O, Brennich ME, Burghammer M, Herrmann H, Köster S
  
• B-crystallin is a sensor for assembly intermediates and for the subunit topology of desmin intermediate filaments. Cell Stress Chaperones 2017; 22:613-626
  Sharma S, Conover GM, Elliott JL, Der Perng M, Herrmann H, Quinlan RA