ترغب بنشر مسار تعليمي؟ اضغط هنا

Unfolding knots by proteasome-like systems: simulations of the behaviour of folded and neurotoxic proteins

476   0   0.0 ( 0 )
 نشر من قبل \\`Angel G\\'omez-Sicilia
 تاريخ النشر 2016
  مجال البحث علم الأحياء
والبحث باللغة English




اسأل ChatGPT حول البحث

Knots in proteins have been proposed to resist proteasomal degradation. Ample evidence associates proteasomal degradation with neurodegeneration. One interesting possibility is that indeed knotted conformers stall this machinery leading to toxicity. However, although the proteasome is known to unfold mechanically its substrates, at present there are no experimental methods to emulate this particular traction geometry. Here, we consider several dynamical models of the proteasome in which the complex is represented by an effective potential with an added pulling force. This force is meant to induce translocation of a protein or a polypeptide into the catalytic chamber. The force is either constant or applied periodically. The translocated proteins are modelled in a coarse-grained fashion. We do comparative analysis of several knotted globular proteins and the transiently knotted polyglutamine tracts of length 60 alone and fused in exon 1 of the huntingtin protein. Huntingtin is associated with Huntington disease, a well-known genetically-determined neurodegenerative disease. We show that the presence of a knot hinders and sometimes even jams translocation. We demonstrate that the probability to do so depends on the protein, the model of the proteasome, the magnitude of the pulling force, and the choice of the pulled terminus. In any case, the net effect would be a hindrance in the proteasomal degradation process in the cell. This would then yield toxicity textit{via} two different mechanisms: one through toxic monomers compromising degradation and another by the formation of toxic oligomers. Our work paves the way to the mechanistic investigation of the mechanical unfolding of knotted structures by the proteasome and its relation to toxicity and disease.



قيم البحث

اقرأ أيضاً

We perform theoretical studies of stretching of 20 proteins with knots within a coarse grained model. The knots ends are found to jump to well defined sequential locations that are associated with sharp turns whereas in homopolymers they diffuse arou nd and eventually slide off. The waiting times of the jumps are increasingly stochastic as the temperature is raised. Larger knots do not return to their native locations when a protein is released after stretching.
Molecular dynamics studies within a coarse-grained structure based model were used on two similar proteins belonging to the transcarbamylase family to probe the effects in the native structure of a knot. The first protein, N-acetylornithine transcarb amylase, contains no knot whereas human ormithine transcarbamylase contains a trefoil knot located deep within the sequence. In addition, we also analyzed a modified transferase with the knot removed by the appropriate change of a knot-making crossing of the protein chain. The studies of thermally- and mechanically-induced unfolding processes suggest a larger intrinsic stability of the protein with the knot.
66 - Cameron Mura 2016
Sm proteins were discovered nearly 20 years ago as a group of small antigenic proteins ($approx$ 90-120 residues). Since then, an extensive amount of biochemical and genetic data have illuminated the crucial roles of these proteins in forming ribonuc leoprotein (RNP) complexes that are used in RNA processing, e.g., spliceosomal removal of introns from pre-mRNAs. Spliceosomes are large macromolecular machines that are comparable to ribosomes in size and complexity, and are composed of uridine-rich small nuclear RNPs (U snRNPs). Various sets of seven different Sm proteins form the cores of most snRNPs. Despite their importance, very little is known about the atomic-resolution structure of snRNPs or their Sm cores. As a first step towards a high-resolution image of snRNPs and their hierarchic assembly, we have determined the crystal structures of archaeal homologs of Sm proteins, which we term Sm-like archaeal proteins (SmAPs).
Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP alpha-synucle in that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent smFRET experiments. We find that alpha-synuclein is disordered with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple alpha-synuclein proteins that may precede amyloid formation.
The total conformational energy is assumed to consist of pairwise interaction energies between atoms or residues, each of which is expressed as a product of a conformation-dependent function (an element of a contact matrix, C-matrix) and a sequence-d ependent energy parameter (an element of a contact energy matrix, E-matrix). Such pairwise interactions in proteins force native C-matrices to be in a relationship as if the interactions are a Go-like potential [N. Go, Annu. Rev. Biophys. Bioeng. 12. 183 (1983)] for the native C-matrix, because the lowest bound of the total energy function is equal to the total energy of the native conformation interacting in a Go-like pairwise potential. This relationship between C- and E-matrices corresponds to (a) a parallel relationship between the eigenvectors of the C- and E-matrices and a linear relationship between their eigenvalues, and (b) a parallel relationship between a contact number vector and the principal eigenvectors of the C- and E-matrices; the E-matrix is expanded in a series of eigenspaces with an additional constant term, which corresponds to a threshold of contact energy that approximately separates native contacts from non-native ones. These relationships are confirmed in 182 representatives from each family of the SCOP database by examining inner products between the principal eigenvector of the C-matrix, that of the E-matrix evaluated with a statistical contact potential, and a contact number vector. In addition, the spectral representation of C- and E-matrices reveals that pairwise residue-residue interactions, which depends only on the types of interacting amino acids but not on other residues in a protein, are insufficient and other interactions including residue connectivities and steric hindrance are needed to make native structures the unique lowest energy conformations.
التعليقات
جاري جلب التعليقات جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
mircosoft-partner

هل ترغب بارسال اشعارات عن اخر التحديثات في شمرا-اكاديميا