The intermediate filament protein consensus motif of helix 2B: its atomic structure and contribution to assembly

Herrmann, Harald; Strelkov, S.V.; Feja, Bernhard; Rogers, Kevin; Brettel, Monika; Lustig, Ariel; Häner, Markus; Parry, David; Steinert, Peter M.; Burkhard, Peter; Aebi, Ueli

doi:10.1006/jmbi.2000.3719

Cited by 137 publications

(157 citation statements)

References 65 publications

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“…Starting with several amino acids preceding the YRKLLEGEESRI motif and through the YRKLL peptide, the coiled-coil structure loosens and the alpha-helices gradually separate eventually bending away from each other at the EGEE level. 33 In vitro data demonstrate that this motif directs the proper formation of tetramers and controls the number of subunits per filament cross section.…”

Section: Molecular Genetics Desmin and The Desmin Genementioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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Section: Molecular Genetics Desmin and The Desmin Genementioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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“…Because of the inability to crystallize intact IF proteins some investigators have taken a "divide and conquer" approach by generating crystals of IF protein fragments or of chimeric proteins that include IF fragments. These data have revealed the structure of small regions containing ␣ helical dimers, including the perplexing "stutter" region within rod 2b (7)(8)(9). The degree to which the crystal structure of the isolated fragments resembles that of those same regions in intact filaments will need to be confirmed.…”

mentioning

confidence: 99%

“…This stripe is the apposing interface between two monomers that assemble into a coiled coil dimer (6). Rigorous demonstration that a particular amino acid or region is ␣ helical or coiled coil has been provided by x-ray crystallography of vimentin fragments and by our initial EPR studies (7)(8)(9)(10).…”

mentioning

confidence: 99%

Structural Characterization of Human Vimentin Rod 1 and the Sequencing of Assembly Steps in Intermediate Filament Formation in Vitro Using Site-directed Spin Labeling and Electron Paramagnetic Resonance

Hess¹,

Budamagunta

Voss

et al. 2004

Journal of Biological Chemistry

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We have previously established the utility of site-directed spin labeling and electron paramagnetic resonance to determine structural relationships among proteins in intact intermediate filaments. Using this same approach we have introduced spin labels at 21 residues between amino acids 169 and 193 in rod domain 1 of human vimentin. The electron paramagnetic resonance spectra provide direct evidence for the coiled coil nature of the vimentin dimer in this region. This finding is consistent with predictions but has never been demonstrated previously. In a previous study we identified residue 348 in the rod domain 2 as one point of overlap between adjacent dimers in intact filaments. In the present study we defined residue 191 in the rod domain 1 as a second point of overlap and established that the dimers are arranged in an anti-parallel and staggered orientation at this site. Finally, by isolating spin-labeled samples at successive stages during the dialysis that lead to filament assembly in vitro, we have been able to establish a sequence of interactions that occurs during in vitro assembly, starting with the ␣ helix and loose coiled coil dimer formation, then the formation of tetrameric species centered on residue 191, followed by interactions centered on residue 348 suggestive of octamer or higher order multimer formation. A continuation of this strategy revealed that both 191-191 and 348 -348 interactions are present in low ionic strength Tris buffers when vimentin is maintained at the "protofilament" stage of assembly.

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“…These two events presumably occur very rapidly in buffers of neutral pH and low ionic strength. On raising the ionic strength, these oligomerize very rapidly perhaps initially into 3-and 4-molecule species, and then into larger half-and full-width unit length filament (ulf) particles containing 8 or 16 molecules, respectively, or more (34,35). The ulf are ϳ70 nm long and 20 nm or more wide.…”

mentioning

confidence: 99%

“…This process occurs in a time frame of seconds to minutes. Also, the growing IF condense to a more uniform and narrower 10-nm diameter (34,35). Thus a protofibril might consist of a column of four rows of molecules.…”

mentioning

confidence: 99%