Why is elastin elastic

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FEBS Lett. Portmann, B. In this model, conformational entropy decreases when the chains are stretched and increases upon relaxation, thereby driving elastic recoil. Consistent with the random network model, we find that the peptide chains in the aggregate are highly disordered. In order to characterize the complex conformational landscape of the disordered ELP chains, we obtained a statistical picture of the different conformational states and interactions accessible to the chains in solution and in the aggregate.

Statistical maps of the two types of peptide-peptide interactions, backbone hydrogen bonds and non-polar side chain contacts, reflect highly-disordered conformational ensembles Figure 2. Secondary structure is sparse and limited to transient sub-ns hydrogen-bonded turns between residues close in sequence near-diagonal elements in Figure 2a,b. As such, our results reconcile spectroscopic evidence for local secondary structure Muiznieks et al.

Probabilistic description of hydrogen bonding top row and non-polar bottom row interactions of SC a and d and MC b and e systems. Panels a , b , d and e are contact maps for pairwise interactions between residues. The color of each square indicates the fraction of conformations in the ensemble for which that interaction is present. Nearest- and next-nearest-neighbour contacts are excluded for clarity in d and e.

Local interactions consist of sparse backbone hydrogen bonds and corresponding non-polar contacts. Non-local interactions consist primarily of non-specific non-polar contacts between side chains. With the absence of preferred non-local interactions, the statistical picture of the conformational ensembles is remarkably simple.

Upon aggregation, local structure propensities are retained as non-local hydrophobic contacts become intermolecular contacts below the diagonal in e. Details of the structural analysis methods are provided in Materials and methods and Supplementary file 1 , Table S2. For example, the VPGV turn has a hydrogen bond between valine 1 and valine 4. Even as it preserves local structural propensities, self-aggregation results in the replacement of non-local intramolecular interactions by intermolecular interactions Figure 2.

In particular, the non-local non-polar contacts that characterize the collapsed isolated chain Figure 2d give way to non-specific interactions with neighboring peptides Figure 2e. The average number of non-polar contacts per chain nearly triples upon self-assembly Figure 2f with a commensurate decrease in the hydration of non-polar sidechains Figure 3b , indicating that the hydrophobic effect strongly contributes to the formation and the structure of the aggregate.

Accordingly, the hydrophobic effect is the major driving force for elastic recoil in several earlier models of elastin Venkatachalam and Urry, ; Weis-Fogh and Anderson, ; Gray et al.

Contrary to these models, however, significant hydrophobic burial is achieved even in the absence of a well-ordered structure. Representative conformation of the aggregate with non-polar side chains yellow , peptide backbone oxygen, red; carbon, white; nitrogen, blue , and hydrogen-bonded water molecules cyan. Peptide chains are shown individually on the periphery with bound water molecules. X HB is the sum of peptide-peptide hydrogen bonds grey and peptide-water hydrogen bonds cyan , for both the SC and MC systems.

Peptide-bound water molecules in the aggregate have fewer neighbors. The lines are shown to guide the eye. While self-assembly effectively buries non-polar side chains Figure 2e,f , disorder of the polypeptide backbone precludes the formation of a water-excluding hydrophobic core.

Since there is only a moderate amount of secondary structure, a majority of backbone peptide groups do not form peptide-peptide hydrogen bonds Figure 2c. Instead, water molecules remain within the aggregate Figure 3a,d,e , Figure 4 in order to satisfy the hydrogen bonding requirements of backbone groups.

As a result, there is little loss of backbone hydration upon peptide self-assembly Figure 3c , even as the side chains become dehydrated Figure 3b. The high degree of hydration of the aggregate In fact, the water content of both the monomer and the aggregate is so high that the probability of any five-residue segment to be completely dehydrated is essentially zero Figure 3—figure supplement 2b.

These results clearly indicate that both systems lack a water-excluding hydrophobic core, a consequence of the high degree of conformational disorder and lack of extended secondary structure imparted by the high proline and glycine content Rauscher et al.

Density profiles for peptide red and water blue as a function of the distance from the center of mass COM of the peptide is shown for the single chain system. Shading in a and b indicates standard error. Note that the large width of the transition region between the homogenous interior and bulk water reflects not only the higher hydration of residues at the surface but also the asphericity of the aggregate see Figure 3—figure supplement 1. The analysis of the average density of peptide and water from the center of mass of the aqueous monomer and of the peptide aggregate quantifies the presence of water throughout the system, even near the center of the peptide, where it represents over 0.

The fact that this value is nearly identical in the monomer and in the aggregate suggests that internal hydration is independent of size and would also be observed in larger and smaller aggregates.

The presence of a plateau in water density indicates that the interior of the aggregate is homogeneous and that the aggregate is large enough to lead to the emergence of bulk-like properties expected of a separate liquid phase. The structural ensemble of the aggregate is disordered Figure 1 , yet contains a significant propensity for secondary structure in the form of transient hydrogen-bonded turns Figure 2b , Table 1 and is highly hydrated Figures 3 and 4.

To understand why aggregation induces peptide expansion Figure 1a , we examine our results in terms of solvent quality. In a poor solvent, solute-solute interactions are energetically more favorable than solvent-solute interactions, leading to a collapse of the polymer chain. Inversely, solvent-solute interactions are preferred in a good solvent, leading to chain expansion. In this minimally-constrained state, the polymer becomes maximally disordered.

Flory, ; Flory, ; Flory, Although disordered protein aggregates have been hypothesized to resemble polymer melts, Fields et al. As a model for this ideal state, we use the residue-specific model for a random-coil polypeptide developed by Flory and co-workers Flory, ; Miller et al. We update their method to include residue-specific transformation matrices derived directly from the simulation data see the detailed description of the method in Supplementary file 1. This result is expected, given the highly hydrophobic composition of the ELP sequence, and the fact that water is a poor solvent for hydrophobic residues.

The internal distance scaling profile of the chain in solution exhibits a slight upturn at large sequence separations. 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. Shading indicates standard error. The dimensions of the chains in the ELP aggregate approach the dimensions predicted for maximally-disordered chains Figure 5 , and therefore the dimensions expected in a polymer melt.

Deviation from ideality reflects the finite size of the aggregate, finite chain length, the presence of local secondary structure Figure 2b , and persistent hydration Figures 3 and 4. These results suggest that elastin—and polypeptide chains in general—cannot make polymer melts in the idealized, solvent-excluding sense because backbone groups must form hydrogen bonds either with each other, which leads to ordering, or with water molecules, whose presence is required for disorder.

Instead, the chains adopt a disordered state with significant backbone hydration, as seen in the representative structures shown in Figure 3a,d and Figure 3—figure supplement 1. 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.

Together, these findings demonstrate how even aggregated peptide chains may approach a state of maximal conformational disorder. The conformational ensembles of the peptide in solution and in the aggregate differ significantly with respect to chain dimensions Figures 1 and 5 , long-range contacts, hydrophobic interactions Figure 2 , and hydration Figure 3. Despite these large global structural differences, the ensembles strongly resemble each other in terms of local secondary structure: the populations and lifetimes of the hydrogen-bonded turns are nearly identical for both SC and MC systems Table 1.

While the dynamics of turn formation are similar, non-local dynamics of the chain differs dramatically in solution and in the aggregate Video 1. Survival probability of the open state without a contact between the chain ends as a function of time for the single chain SC a and for the aggregated chains MC b.

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Each of the 27 peptide chains is colored individually. Frames in the movie correspond to conformations separated by 50 ps time intervals. A smoothing window of 2 frames was applied and all conformations were aligned to the first conformation for clarity using VMD Humphrey et al. As can be seen in the movie, both the global structure of the entire aggregate as well as the conformation of individual chains within the aggregate fluctuate on the nanosecond timescale.

Chains on the surface of the aggregate occasionally extend outward into the surrounding water water molecules are not shown for clarity. Reptation theory predicts characteristic signatures for the dynamics of polymer chains in melts de Gennes, : short timescale motions are predicted to obey Rouse-like dynamics, whereas long timescale motions should be strongly affected by the confinement imposed by neighbouring chains.

To determine whether the dynamics of aggregated elastin peptides is characteristic of a melt, we analyzed the diffusion of the central residue of each chain Figure 6—figure supplement 1. This value is similar to the exponent close to 0. The chain length used here may be too short to observe this crossover.

Consistent with this hypothesis, Ramos et al. Ramos et al. The absence of crossover may also be due to insufficient simulation length, or to the fact that the chains remain highly hydrated in the aggregate and are not characteristic of a solvent-excluding melt.

Despite the moderate size of our aggregate, its melt-like properties suggest that the present study captures the fundamental basis for ELP phase separation. As such, the molecular basis for phase separation uncovered in this study is likely to be relevant to longer ELPs and full-length tropoelastin. In support of this point, our results are in excellent agreement with a recent NMR study of block peptides with alternating cross-linking domains and hydrophobic GVPGV 7 domains, successively in solution, in the coacervate, and in materials produced by cross-linking Reichheld et al.

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.

The unusual properties of elastin and ELPs set them apart both from more common types of intrinsically disordered proteins IDPs that do not self-aggregate, and from proteins that form amyloid upon aggregation. On the one hand, the majority of IDPs have a high charge content and low sequence hydrophobicity, which allows them to avoid self-aggregation Uversky et al.

Several computational studies have described structural ensembles of the more common type of IDPs. Among them, the RS peptide, which has a high net charge, was studied in detail using both simulations and experiments Rauscher et al. Extensive computational studies of IDPs with varying fraction of charged residues have been carried out Das and Pappu, It has been postulated that the interaction between tropoelastin and cell surface proteoglycans is part of the assembly process of elastin before it is deposited on microfibrils.

Fibrillin-1 and -2 also interact with proteoglycans Tiedemann et al. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin Lee et al.

Instead, tropoelastin domains 14—18 and 36 RKRK sequence have been found to bind to both integrins. The lysines of domain 15 and 17 are believed to play key roles in this interaction.

Furthermore, as integrins are involved in the remodeling of the ECM Bonnans et al. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. For many years it was difficult to study tropoelastin at an atomic scale, but the application of computational methods, such as full-atomistic molecular dynamics and elastic network models, in combination with powerful low-resolution structural studies, have expanded the field and delivered an enhanced understanding of the mechanisms that contribute to self-assembly.

Modeling has been verified using wet-bench methodologies, forming a robust suite of complementary methodologies that will undoubtedly become more prevalent for exploring the assembly of biological fibers over time. With leaps in the improvement of cryogenic electron microscopy to characterize flexible molecules, we predict that this approach will contribute to a deeper understanding of tropoelastin structure and self-assembly in the context of endogenous fiber formation and biomaterials fabrication.

The authors wrote and submitted this manuscript in response to an invitation by the Editor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aaron, B. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers.

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Tropoelastin massively associates during coacervation to form quantized protein spheres. Biochemistry 45, — Cordier, P. Self-healing and thermoreversible rubber from supramolecular assembly.

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In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Hinek, A. Recycling of the kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. Cell Res. Hu, Q. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes.

Indik, Z. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Jensen, S. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Kadler, K. Fell muir lecture: collagen fibril formation in vitro and in vivo. Procedures such as injections of collagen and hyaluronic acid to rejuvenate skin have been developed, but there are currently no approved devices to introduce functional elastin into the skin.

Elasticity is considered a marker of overall skin health, 12 and elastin production is fundamental to the resilience of tissues and organs. Treatments that could replenish or replace elastin and elastic fibers are a logical approach to maintaining healthy skin. This review focuses on the clinical relevance of elastin to the structure and function of skin, highlighting the importance of elastin during wound healing, scarring, and aging, as well as new treatment approaches aimed at replenishing or repairing the skin elastic fiber network.

Furthermore, the high content of short-chain hydrophobic amino acids in tropoelastin, in concert with water, contributes to the capacity for elasticity and recoil in the skin.

Elastic fibers are formed through a complex process known as elastogenesis Figure 1. Elastogenesis hinges on the availability, assembly, and crosslinking of its dominant component, tropoelastin. Elastogenesis begins when soluble tropoelastin monomers are secreted by fibroblasts into the extracellular environment, where they bind to the fibroblast through specific cell surface interactions. After binding, tropoelastin aggregates into microscopic globules in an initial microassembly phase 18 in which the tropoelastin monomers rapidly align and concentrate.

The crosslinked bundles of tropoelastin remain bound to the cell surface, where additional tropoelastin is added as elastin is formed and gradually deposited onto fibrillin-rich microfibrils until a nascent elastic fiber is produced and released from the cell surface.

Role of tropoelastin in elastogenesis and the production of elastic fibers. A Assembling tropoelastin coalesces into to nm nanoparticles that remain on the elastogenic cell surface soon after secretion. E Lysyl oxidase and lysyl oxidase-like proteins oxidize lysine residues in tropoelastin before and during coacervation, allowing for F their covalent crosslinking into elastin.

Reprinted from Matrix Biology , vol. Copyright , with permission from Elsevier. Skin aging, both intrinsic and extrinsic, results in wrinkled skin with decreased elasticity. Elastin and elastic fibers are unique in that there is very low and slow turnover.

In fact, in skin, the overall half-life of elastin is similar to the human lifespan! Elastolytic enzymes called elastases, which arise from disease, sun exposure, free radical damage, inflammation, and other conditions, degrade elastin fibers. These disruptions occur in 2 main ways: first, the elastic fibers shorten and fragment; and second, damage accumulates to the protein through modification of aspartic acid residues, calcium and lipid accumulation, and glucose-mediated crosslinking.

Considering that production of new elastin ceases in maturity, 4 and tropoelastin synthesis does not obviously recur unless wound healing occurs, there is a need to identify treatments that can either replenish or stimulate production of tropoelastin or elastin in a structurally appropriate way in the skin, so that skin elasticity can be preserved.

Genetically acquired defects in elastin can result in diseases associated with the loss of skin elasticity. Elastic fiber networks also degenerate during wound healing, scarring, and photoaging ie, chronic sun exposure. Injury to the skin compromises the integrity and structure of the skin, resulting in a tightly regulated response near the injury to remove any foreign material, prevent infection, and heal the wound.

There are 4 main processes in wound healing in adults: hemostasis, inflammation, proliferation, and remodeling. Then, vascular granulation tissue, rich in chondroitin sulfate, and a mix of proteoglycans, such as decorin, associates with collagen fibers and versican, which associates with elastic fibers. This step is followed by deposition of the provisional type III collagen-rich matrix, finally followed by deposition of mature type I collagen that changes throughout the remodeling phase.

Elastic fibers are the last extracellular matrix fibers that may form in small amounts. The culmination of these processes results in scar tissue with a large amount of deposited collagen with abnormally arranged, often large, collagen bundles. Elastin contributes to wound healing not only by providing mechanical elasticity, but also by acting on cells that gradually reduce wound contraction and improve regeneration of the dermis. Elastin production decreases as age increases. Degradation and disorganization of the components that make up elastic fibers contribute to the development of atrophic depressed , hypertrophic raised , and keloid overgrown scars.

Striae distensae alba typically appear as atrophic dermal scars where gaps are filled with new, disorganized collagen and elastin. Aging skin and skin exposed to substantial sun damage presents with a changed structure to that of younger, healthier skin. In photoaged skin, these changes include coarse wrinkling, roughened texture, sallow complexion, mottled pigmentation, and marked loss of elasticity, whereas intrinsically aged skin exhibits fine wrinkling, smooth texture, clear complexion, uniform pigmentation, and gradual loss of elasticity.

Laser scanning confocal microscopy shows the 3-dimensional arrangement of both collagen and elastic fibers in sun-protected versus photodamaged skin Figure 2 , demonstrating profound differences in the superficial dermis. Confocal scanning laser microscopy is used to compare sun-protected to sun-damaged skin from the same individual.

A Collagen immunostaining red reveals a dense network of collagen fibers arranged parallel to the epidermis that are brightly stained immediately beneath the unstained epidermis. B Photoaged skin from the same individual reveals a decrease in collagen fibers and a deteriorated architecture to the fibers that remain. C Elastin staining green of sun-protected skin reveals a rich network of elastic fibers perpendicular to the epidermis in the superficial dermis, and parallel to the epidermis in the deeper dermis.

D Elastin staining in sun-damaged skin from the same individual reveals an absence of the vertical elastic fibers as well as large clumps of nonfunctional solar elastotic material.

E Dual immunostaining for collagen and elastin are superimposed to demonstrate the interaction of collagen and elastic fibers in sun-protected skin. F The dramatic alterations of collagen and elastic fibers are seen in photoaged skin. Dermoepidermal junction is marked by. Long-term sun exposure alters the collagen of the papillary dermis. Comparison of sun-protected and photoaged skin by northern analysis, immunohistochemical staining, and confocal laser scanning microscopy.

J Am Acad Dermatol. Chronic sun exposure disrupts the elastic fiber architecture in substantial ways, resulting in an accumulation of elastin-containing material below the dermal-epidermal junction, known as solar elastosis, leading to the loss of skin elasticity. In addition, the normal oxytalan fibers that extend vertically to the epidermis and contain fibrillin, but not elastin, are degraded and often absent in photodamaged skin.

Microfibrillar components of elastic fibers are susceptible to damage by UV radiation, which may contribute to the demise of elastic fiber networks in photoaged skin.

A Sun-protected buttock skin stained with Verhoeff-van Gieson stain, showing collagen fibers in red and elastic fibers in black and demonstrating a collagen-rich dermis with the fine meshwork of elastic fibers.