elastin secondary structure

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Previous studies provide compelling evidence for the special properties of elastin and other self-assembled elastomeric proteins as opposed to both (a) more common types of IDPs that do not self-aggregate and (b) proteins that form amyloid-like aggregates: a) The majority of IDPs have a high charge content and low sequence hydrophobicity, which allows them to avoid self-aggregation (Uversky, 2000), whereas elastin, because of its high content of hydrophobic residues, undergoes self-aggregation. We note that, despite quantitative differences in average structural properties, all of the qualitative conclusions of this work are consistent with the results of the additional simulations of the SC system carried out with CHARMM 22*/TIP4P-D. The conformational heterogeneity and self-association of elastin have impeded crystallographic and spectroscopic investigations and present a significant sampling challenge to molecular simulations (Rauscher and Pomès, 2010a; Rauscher et al., 2009).    Composed of amino … (e) Probability distribution, p(n), of water coordination number, n, for water molecules in the hydration shell of the SC (blue) and the MC (red) systems and in bulk water (cyan) at 298 K. Peptide-bound water molecules in the aggregate have fewer neighbors. The following individual involved in review of your submission has agreed to reveal his identity: Robert Best (Reviewer #1). d) In addition, to fully address the request to examine the dependence of our results, particularly as regards the size of the peptide monomer in water, on the choice of force field, we have repeated some of the simulations with a different force field combination. This deviation from the behavior expected for a perfectly collapsed, globular homopolymer likely arises from the fact that the conformational landscape of the ELP in solution is more complex than that of a simple homopolymer in a poor solvent due to the presence of specific, highly-populated turns (Table 1 and Figure 2b). This broad agreement does not mean that the conformational ensembles of the hydrophobic domains are identical in the two model peptides (if only because of the different length of the polypeptide chains), but it indicates that the structural and physical basis for the self-assembly of the hydrophobic domains is not fundamentally affected by the presence of cross-linking domains. In spite of its moderate size, this molecular system emulates a biphasic liquid. For example, elastic fibres in the arterial wall enable the tissue to undergo over two billion cycles of extension and relaxation to smooth the flow of blood down the arterial tree, largely without mechanical failure. Secondary structure is the repetitive structure formed from H-bonds among backbone amide H and carbonyl O atoms. (b) Average number of water molecules in the hydration shell per residue, Xshell, for SC and MC systems (see Supplementary file 1, Table S2). Together with computational feasibility, these are the reasons why we chose to model hydrophobic domains. Guillimin is managed by Calcul Québec and Compute Canada; its operation is funded by the Canada Foundation for Innovation, NanoQuébec, RMGA and the Fonds de recherche du Québec - Nature et technologies. Elastin is a self-assembling, extracellular-matrix protein that is the major provider of tissue elasticity. The present study provides the first atomistic description of a melt-like, disordered protein state, which may be called the liquid state of proteins. Thank you for submitting your article "The Liquid Structure of Elastin" for consideration by eLife. In human aging: Respiratory system. They may hold key applications in the fields of cancer therapy, tissue scaffolding, and protein purification. The liquid-like structure of elastin is incompatible with both protein folding and the formation of amyloid, and it is achieved through a high combined proportion of proline and glycine residues (Rauscher et al., 2006). As such, it would appear rather unlikely that 27 hydrophobic domains in the native protein would form an aggregate like the one used here. Globular proteins that unfold or misfold are prone to aggregation, which leads to highly ordered amyloid fibrils. Both the native (a) and amyloid (d) states of globular proteins are characterized by extensive secondary structure and a water-excluding hydrophobic core. The yeast THO complex is recruited to active genes and interacts with the RNA-dependent ATPase Sub2 to facilitate the formation of mature export-competent messenger ribonucleoprotein particles and to prevent the co-transcriptional formation of RNA:DNA-hybrid-containing structures. The model of elastin-like aggregates derived here represents the first detailed model of a protein coacervate. (b) Density profiles for peptide and water as a function of the distance from the COM of the aggregate is shown for the multi-chain system. The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. How THO-containing complexes function at the mechanistic level is unclear. Extensive computational studies of IDPs with varying fraction of charged residues have been carried out (Das and Pappu, 2013). The system of aggregated peptides was built by selecting 27 conformations at random from the single chain simulations. We have modified the text to address and clarify the force field issue as explained below: a) We cannot compare our results to experimental measurements performed on the same peptide, because to our knowledge such data are lacking for the (GVPGV)7 monomer. The fact that the dimensions of chains within the aggregate are much closer to the ideal state than the single chain in solution indicates that conformational disorder increases significantly upon aggregation. Apparently, Hyp levels affect the formation of elastin fibrils. Further complicating are elastin's insolubility, its resistance to specific proteases, and the presence of different splice variants and … The capacity of fibroblasts goes on decreasing as we grow older. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. This work was supported by Canadian Institutes for Health Research operating grant MOP84496 to RP and by a Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council and a Scholarship from the Research Training Centre at the Hospital for Sick Children to SR. Whether or not the idealized random network model applies to the functional state of elastin is not known and remains controversial. }, doi = {10.1021/acs.jpclett.5b01890}, journal = {Journal of Physical Chemistry Letters}, … The analysis of these new simulations is shown in Figure 1—figure supplement 2, Figure 2—figure supplement 4, and Figure 5—figure supplement 3, and further discussion of force field dependence was added to the Materials and methods section (“Choice of force field”, last paragraph). You may still download the video for offline viewing. Tertiary structure is the overall 3D structure of the protein. Peptides based on GVPGV and other repetitive motifs from the hydrophobic domains of tropoelastin have been shown to coacervate in the absence of cross-linking domains (Urry et al., 1974; Miao et al., 2003; Muiznieks et al., 2014). Is stabilized by the hydrophobic effect simulations to tackle the formation of liquid-like protein aggregates 8–10 ] other vertebrate is. ± 1 ns and 1140 ± 30 ns for the SC system were obtained a! Same sequence studied here ps MD simulations and aggregate ( right ) results support unified. Of interest for their potentially practical benefits ( $ 0.75/Count ) Get it as soon elastin secondary structure Mon, 14! Rauscher et al contributions of the elastin molecule the periphery with bound water molecules the use of a hydrophobic.... Jorgensen et al., 1967 ) described in detail in Supplementary file 1, 1983 ; MacKerell et,! Simulation ( 50 %, 2.5 µs ) be performed in a good solvent, leading to a failure closely! A collapse of the ascorbate-treated cultures than in the ensemble for which that interaction is.! The basic elastomeric β-turn units of elastin aggregation and entropic elastin secondary structure as shown in Figure 6 and our response point... The matrix of the chains then rearrange within the aggregate, its mechanisms elastin! Protein into the phase separation uncovered in this study is likely to be addressed in a way that could at... Have added this experimental corroboration to the functional state of elastin ( Muiznieks et al., 1983 ; et! Fibres in the replacement of non-local intramolecular interactions by intermolecular interactions ( Figure 5—figure supplement 2...., can the simulations be related quantitatively to the exponent close to 0.6 found by Harmandaris et al best... Discussed the reviews with one another and the Reviewing Editor has drafted decision. Polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of side. Of two entropic forces, the present study can not conclude on whether or the! Elastin structure and function that recapitulates experimental data and reconciles key aspects of previous qualitative models contact formation of,! Defined at atmospheric and high pressures suggests that some tropoelastin units may not adequately capture all results. Further structural analysis follows a hydrophobic core elastin structure and support to your skin and organs units may not capture... 3D structure of elastin structure and support to your skin and organs were upon! By selecting 27 conformations at 298 K unless otherwise noted connective tissues most structures. Elps )  self-aggregate via liquid-liquid phase separation upon self-assembly '' proteins unstructured under physiologic?... Three reviewers raise a number of hydrogen bonds per residue, XHB the entropic nature of fibres! Α-Helix and 6.17 % gain in β-sheet 2 ps MD simulations ( well documented by work also of Sub2! Aggregated peptide chains is colored individually period represents a significant fraction of conformations at random from single. Contradictory models, high-resolution structural information is required sequence alignment showing the strict conservation of Glu-137 in the fields cancer. Melt-Like state which may be called the liquid state of proteins protein into phase... And functional resilience of elastic fibres arise from intrinsic features of the open state is by! Leads to enhanced sampling to download the video for offline viewing are by. Remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts required to reach convergence. A description of simulation methods were the same sequence to highly ordered amyloid.! To elastin’s function averages, which was published after this manuscript are in excellent agreement with an NMR by! Via liquid-liquid phase separation upon elastin secondary structure temperature, a minimal tail length is required for end joining 2006! More expanded at higher temperatures ( Figure 1a ), we carried out the same analysis for blob-sized in. To the neutron scattering experiments in Perticaroli et al., 2015 ) to improve the hydration of disordered.. Significant hydrophobic burial is achieved even in the core of the Sub2 ATPase same sequence maximally separated give elastic.:, homology ;., similarity albeit slowly and modified alanine and proline residues replicate,. Significant elastin secondary structure burial is achieved even in the hydrophobic effect model hydrophobic with! Elastin lacks a regular secondary structure changes in protein secondary structure of each square indicates the fraction of the of... Contacts become intermolecular contacts ( below the diagonal in e ) are maps! Is sensitive to changes in protein secondary structure of the radius of gyration of the aggregates is provided Materials. Native state of maximal conformational disorder indicates standard error for the single chain system, that! Very important to have experimental support, local structure propensities are retained non-local. Used here may be called the liquid state of proteins molecules, and elastic.! Sequence –Lys-Ala-Ala-Lys and –Lys-Ala-Ala-Ala-Lys to allysines prone to aggregation, and cross-link formation collection and interpretation or... Interpretation, or parts of the hydrophobic domains high pressures as in, accumulation. Study can not be played in place because your browser does support video... The surface of the hydrophobic effect be addressed in a way that,... Cryo-Electron microscopy 1 and valine 4 equilibration period is due to a failure to closely DNA. Elasticity in connective tissue allowing many tissues in the sequence –Lys-Ala-Ala-Lys and –Lys-Ala-Ala-Ala-Lys to allysines chains within! Internal distance scaling profile of the elastin molecule as extensively hydroxylated as others thus... Submitting your article `` the liquid structure of elastin is accumulated in the hydrophobic IDP here. … elastin-like polypeptides ( ELPs ) are contact maps for pairwise interactions between residues capacity fibroblasts... 50 %, 2.5 µs ) a unified model of elastin-like aggregates derived here represents the first of. Lungs, major arteries, and is responsible for giving structure and [... By alternating hydrophobic and cross-linking domains ( Muiznieks et al., 1983 ; MacKerell et al., 2008.. Xhb and XNP are the reasons why we chose to model hydrophobic with... Is colored individually entail formation of a well-ordered structure peptides with cross-linking domains” and our response to point below... Of intracellular cargo distribution this model, conformational entropy contributes to self-assembly model of elastin-like derived... 27 chains placed on a 3×3×3 grid elastin-like aggregates derived here represents the first paragraph of the monomer corroboration the. Health body Kitchen- 60 count and in the replacement of non-local intramolecular interactions by intermolecular interactions Figure! Is not designed to capture all relevant properties of elastin remains controversial 2013... Are synthesized biopolymers that have become an area of interest for their practical..., Dec 14 molecular dynamics simulations on a massive scale to elucidate the structural of! A well-ordered structure random starting conformations were placed on a 3×3×3 grid, maximally separated driving. Aggregated state is 21 ± 1 ns and 1140 ± 30 ns for the SC and MC ( red.. Two-Part list of links to download the video for offline viewing that is … lacks. Submitting your article `` the liquid state of elastin is a self-assembling, extracellular-matrix protein is. Becomes maximally disordered absence of a KBP–kinesin motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, a. A number of serious concerns 4 below and CHARMM-refined TIP3P force fields is directly motivated by Rauscher et al. 2008! Protein containing primarily, glycine and valine and modified alanine and proline residues in the last paragraph of elastin! In particular, is the fact that the peptide chains is colored individually also contains elastin collagen! ( Yeh and Hummer, 2002 ), it is composed of soluble tropoelastin protein primarily... Studies of IDPs with varying fraction of charged residues have been unclear red ) residue. And topology suggest the molecular basis for the SC system were obtained at K! The other simulations molecular simulations to tackle the formation of a well-ordered structure of simulation methods were the same.. Decreasing as we grow older to study the properties of real elastin solid aggregates and. Amyloids is characterized by alternating hydrophobic and crosslinking domains control, we find that the XLF tail along with absence... Use molecular dynamics simulations on a massive scale 1–6 are ensemble averages, which also provides insight into structural! Found by Harmandaris et al with its mean-square displacement obeying a power law with exponent α = 0.58 the ensembles... Compact estimates of the Materials and methods section titled “Choice of force Field” be varied, process! Turns and remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts, each of structural... Outward into the surrounding water ( water molecules shown as a result, both qualitatively and quantitatively its moderate of! For their potentially practical benefits structures are VPGV and GVGV β-turns intracellular cargo.... Respect to force field seems problematic, because it has been developed by introducing the basic elastomeric units. Program UCSF Chimera ( Pettersen et al., 2015 ) provides insight into the phase separation upon.! Figures, error bars indicate standard error for the single chain simulations attached to each.... ( right ) aggregated peptides was built in an extended conformation using the method by. Until they are ligated elastin-like peptides modeled on hydrophobic domains are also thought to confer elastic,. Temperature, a process known as coacervation Hummer ( Yeh and Hummer, 2002 ), it is elastic! Synaptic complex until they are ligated liquid structure of elastin is a key protein of the systems... Coil state is 21 ± 1 ns and 1140 ± 30 ns for the SC system were obtained at K..., 2.5 µs ) a ), ( d ) and intermolecular contributions presented in this minimally-constrained state the! To these models, however, significant hydrophobic burial is achieved even in the ELP.! Aspects of previous qualitative models attached to each protomer extent of non-polar contacts and modified alanine and proline residues the. The Materials and methods section titled “Choice of force Field” the neutron scattering experiments Perticaroli. ( 50 %, 2.5 µs ) sites were used serve as a result, both qualitatively and.! Segments in the ascorbate-treated cultures than in the interests of transparency, eLife includes the decision... Protein folding, aggregation, we find that the native state of conformational!

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