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Mutations in Desmin's Carboxy-Terminal “Tail” Domain Severely Modify Filament and Network Mechanics

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Mutations in Desmin's Carboxy-Terminal “Tail” Domain Severely Modify Filament and Network Mechanics doi:10.1016/j.jmb.2010.02.024 J. Mol. Biol. (2010) 397, 1188–1198 Available online at www.sciencedirect.com Mutations in Desmin's Carboxy-Terminal “Tail” Domain Severely Modify Filament and Network Mechanics Harald Bär1,2†, Michael Schopferer3†, Sarika Sharma1,2, Bernhard Hochstein3, Norbert Mücke4, Harald Herrmann2 and Norbert Willenbacher3⁎ 1Department of Cardiology, Inherited mutations in the gene coding for the intermediate filament protein University of Heidelberg, desmin have been demonstrated to cause severe skeletal and cardiac 69120 Heidelberg, Germany myopathies. Unexpectedly, some of the mutated desmins, in particular those carrying single amino acid alterations in the non-α-helical carboxy- 2Group Functional Architecture terminal domain (“tail”), have been demonstrated to form apparently of the Cell, German Cancer normal filaments both in vitro and in transfected cells. Thus, it is not clear if Research Center, filament properties are affected by these mutations at all. For this reason, we 69120 Heidelberg, Germany performed oscillatory shear experiments with six different desmin “tail” 3Institute of Mechanical Process mutants in order to characterize the mesh size of filament networks and Engineering and Mechanics, their strain stiffening properties. Moreover, we have carried out high- University of Karlsruhe, frequency oscillatory squeeze flow measurements to determine the bending Gotthard-Franz-Straße 3, 76131 stiffness of the respective filaments, characterized by the persistence length Karlsruhe, Germany lp. Interestingly, mesh size was not altered for the mutant filament 4 networks, except for the mutant DesR454W, which apparently did not Division of Biophysics of form proper filament networks. Also, the values for bending stiffness were Macromolecules, German “ ” – μ in the same range for both the tail mutants (lp =1.0 2.0 m) and the wild- Cancer Research Center, μ type desmin (lp =1.1±0.5 m). However, most investigated desmin mutants 69120 Heidelberg, Germany exhibited a distinct reduction in strain stiffening compared to wild-type Received 25 August 2009; desmin and promoted nonaffine network deformation. Therefore, we received in revised form conclude that the mutated amino acids affect intrafilamentous architecture 25 January 2010; and colloidal interactions along the filament in such a way that the response accepted 12 February 2010 to applied strain is significantly altered. Available online In order to explore the importance of the “tail” domain as such for 18 February 2010 filament network properties, we employed a “tail”-truncated desmin. Under standard conditions, it formed extended regular filaments, but failed to generate strain stiffening. Hence, these data strongly indicate that the “tail” domain is responsible for attractive filament–filament interactions. Moreover, these types of interactions may also be relevant to the network properties of the desmin cytoskeleton in patient muscle. © 2010 Elsevier Ltd. All rights reserved. Keywords: modifications in desmin filament and network mechanics due to Edited by M. Moody mutations; electron microscopy; rheology; persistence length; strain stiffening Introduction interconnected cytoplasmic filament network.1 Muta- tions in the gene coding for the muscle-specific IF In animal cells, microfilaments, microtubules, and protein desmin cause desminopathy, a subset of myofibrillar myopathy. This severe muscle disease intermediate filaments (IFs) constitute a dense, tightly – can affect both skeletal and cardiac muscles.2 4 One hypothesis raised previously was that these muta- tions would render the mutant desmin protein *Corresponding author. E-mail address: assembly incompetent and would consecutively [email protected]. cause the misfolded protein to be segregated into † H.B. and M.S. contributed equally to this work. large intracellular aggregates—the characteristic his- Abbreviations used: IF, intermediate filament; PBS, tological finding in affected muscle.5 However, this phosphate-buffered saline. theory may have to be modified and extended, as 0022-2836/$ - see front matter © 2010 Elsevier Ltd. All rights reserved. Mutations in Desmin's Carboxy-Terminal Tail Domain 1189 extensive analyses involving recombinant wild-type shear experiments, to characterize the biophysical and mutant desmin proteins and transfection studies properties of filament networks formed by the in several cell lines revealed that part of the mutations respective recombinant mutant proteins. Recent does not impair the filament assembly of the analyses of the viscoelastic properties of both wild- respective mutant desmin variants both in vitro and type desmin and vimentin filament networks – in vivo.6 8 In particular, mutations residing in illustrated the potential of these techniques to desmin's carboxy-terminal non-α-helical “tail” do- characterize the viscoelastic mechanical properties main were shown to be mostly assembly competent.9 of these “biopolymers” in solution.16 Oscillatory These findings immediately offer a more complex shear experiments at constant frequency and varying model of the development of disease in desmino- stress amplitudes have been used to characterize the pathy: mutant desmin variants that allow filament mesh size and strain stiffening properties of the formation are now believed to impact on desmin filament network, while the bending stiffness of function at a higher-order level, either by altering the individual filaments in solution has been deduced “intrinsic” biophysical properties of the filament from small-amplitude high-frequency oscillatory itself or by changing binding properties towards squeeze flow measurements. In order to understand associated proteins (“extrinsic” filament pro- the influence of the “tail” domain as such on the perties).1 The former hypothesis has only recently filament's viscoelastic properties in detail, we addi- gained support from investigations on the nano- tionally analyzed a tail-deleted desmin variant. mechanical properties of individual desmin IFs Our findings show that the tail domain is indeed through stress measurements using the tip of the important for establishing desmin's characteristic cantilever of an atomic force microscope.10 Just as mechanical filament properties and that mutations well, the latter hypothesis was strengthened sub- can significantly change “intrinsic” filament pro- stantially through the finding that the assembly- perties without altering the filament morphology, as competent desmin mutant DesE245D alters the revealed by high-resolution electron microscopy. interaction of desmin with nebulin and thereby Given the important role that desmin IFs play as directly influences microfilament architecture.11 mechanosensor and mechanotransducer within The focus of the present study was to analyze the myocytes, we speculate that these profound altera- impact of mutations in the carboxy-terminal non-α- tions in the nanomechanical properties of desmin helical “tail” domain of desmin on the biophysical have clinical relevance and might contribute to properties of filament networks in bulk solution. disease development. These mutations were chosen as we could recently demonstrate that all of them assembled into filaments both in vitro and in transfected myoblasts, Results and Discussion although with different efficiencies.9 As the ob- served disease phenotype in patients carrying these mutations is as severe as that for mutations that Filament assembly in vitro render the desmin protein completely assembly incompetent, part of the mechanisms underlying In order to visualize the polymerized mutant the development of severe myopathy may lie in desmin variants analyzed by rheometry, we have alterations in the properties of filaments due to assembled the respective proteins at the concentra- single amino acid exchanges. Accordingly, it has tion employed in rheological experiments (i.e., at been pointed out earlier that mutations in another IF 1.0 g/l). After fixation and dilution of the samples to system (i.e., keratins) can alter the mechanical 0.1 g/l, filaments were negatively stained, and properties of their networks substantially.12 Espe- filament width was measured by electron micros- cially, the non-α-helical tail domain has been shown copy. The tail-truncated desmin variant (DesΔTail) to have a strong impact on the bundling and strain is capable of forming bona fide IFs, which, when stiffening of keratin networks.13,14 However, the compared to wild-type desmin (DesWT), are slightly assembly reaction of keratins, forming complex more irregular (Fig. 1a) but of similar diameter networks in epithelia, differs considerably from (Table 1). As previously documented,9 all mutant that of IF proteins such as vimentin and desmin.15 desmin variants, except for DesR454W, are able to Hence, under conditions where vimentin and form extended filamentous networks. Assemblies of desmin do not organize above tetramers and DesR454W exhibit defective longitudinal annealing octamers, keratins assemble into huge networks; properties and, thus, only short filamentous struc- moreover, keratin IFs have a tendency to bundle tures were observed (Fig. 1b). Upon copolymeriza- massively,14 a property not observed with vimentin tion with an equimolar ratio of wild-type desmin, anddesminevenathighproteinandsalt most mutants are capable of filament formation. concentrations.16 Therefore, the detailed interactions Quite remarkably, however, the equimolar mixture of keratins and desmin, respectively, in higher-order
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