February 14, 2018 Michael Patrini. Biotechnol., 25 February 2021, View all Sci. For this injection, the researchers used a new . J. Biochem. Genet. Tropoelastin was revealed to be an asymmetric molecule with distinct N- and C-terminal regions that are respectively referred to as the head and foot of the molecule. Rep. 8, 116. Identification of an elastin cross-linking domain that joins three peptide chains. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. The tropoelastin that Elastagen manufactures is an identical copy of what naturally occurs in human tissue, meaning the clinical application opportunities for this has tremendous potential . (2016). J. Biol. Eng. Elastin and other dermal components are gradually lost through aging, sun damage, and following injury, highlighting a need to replace these components to repair the skin. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. Co-author Professor Anthony Weiss from the Charles Perkins Centre and Faculty of Science explained: "Tropoelastin can repair the heart because it is a precise replica of the body's natural elastic protein,". Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Cell Biol. A., Gray, W. R., and Franzblau, C. (1973). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. This canonical computational structure was determined to be highly similar to the envelope found via SAXS/SANS, where both consist of an extended molecular body accompanied by a protruding foot (Baldock et al., 2011). Cooperativity between the hydrophobic and cross-linking domains of elastin. J. Biol. doi: 10.1016/j.matbio.2006.08.258, Clarke, A. W., Arnspang, E. C., Mithieux, S. M., Korkmaz, E., Braet, F., and Weiss, A. S. (2006). Cytochem. Mater. The advantage of coarse-grained methodologies is that they allow for the simulation of timescales of large molecular systems on the order of microseconds, which are otherwise computationally infeasible with classical full-atomistic molecular dynamics. U.S.A. 109, 28782883. Acad. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late B., Broekelmann, T. J., et al. Integrins are a major class of cell surface receptor family, of which tropoelastin has been found to interact with two types: v3 (Rodgers and Weiss, 2004) and v5. 252, 351365. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Chem. J. Biol. Biol. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Pharmacol. J. Biol. J. Biol. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). Earnings, adjusted for non-recurring costs, came . 278, 4855348562. Chem. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. A., and Rucker, R. B. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. J. Biol. 37, 698702. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Biopolymers 20, 12471260. Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). 250, 9298. (2019b). Matrix Biol. J. Biol. J. Biol. The lysines of domain 15 and 17 are believed to play key roles in this interaction. Biomacromolecules 21, 35233538. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. J. Mol. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). [Epub ahead of print]. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). doi: 10.1016/j.matbio.2019.06.010, Reichheld, S. E., Muiznieks, L. D., Stahl, R., Simonetti, K., Sharpe, S., and Keeley, F. W. (2014). Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Proc. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). FEBS Lett. (2006). Tropoelastins flexibility does not allow it to pack into a crystal lattice and its size renders it too complex to assign atomic interactions using nuclear magnetic resonance (NMR) on a global level (Tamburro et al., 2003, 2006; Bochicchio et al., 2004; Pepe et al., 2008). AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. 29, 152159. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. The alignment of these three domains indicates that at least two tropoelastin molecules are required to form this tetrafunctional cross-link, thus, giving rise to the head-to-tail model of assembly involving the growth of a linear chain that can assemble laterally to form sheets and eventually form spherules (Baldock et al., 2011). Self-healing and thermoreversible rubber from supramolecular assembly. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Mol. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Acta 761, 1722. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. 34, 8190. 126, 563574. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. No use, distribution or reproduction is permitted which does not comply with these terms. J. Biochem. Thus, computational approaches can be considered as important means to complement wet bench experiments. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. Biochemistry 45, 95189530. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. It has recently been suggested that fibrillins are capable of stabilizing tropoelastin, possibly for the purpose of selecting conformations that are favorable for elastin assembly (Lockhart-Cairns et al., 2020). 589(19 Pt A), 24772486. Biophys. Nature 451, 977980. 82, 335340. (2008). On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. 410, 317323. Elastin is one of the most abundant proteins in your body. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. Biochem. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. (2018). Chem. Characterization of the complete human elastin gene. Fell muir lecture: collagen fibril formation in vitro and in vivo. Engineering a highly elastic human protein-based sealant for surgical applications. Proc. Our Juvederm collection of fillers has sales of over $1 billion globally and is one of the fastest growing parts of our Aesthetics business, said Bill Meury, Chief Commercial Officer at Allergan. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. U.S.A. 110, 28522857. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). 2:e1501145. Structural changes and facilitated association of tropoelastin. Molecular docking studies utilizing tropoelastin and the 3D structure of LOX1 (Vallet et al., 2018) may assist in our understanding as to whether the enzyme has a preference for modifying particular tropoelastin residues. Investig. 87, 18281834. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Pediatr. (1989). Biopolymers 29, 16991706. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. 41, 494497. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Acta Gen. Subj. Figure 1. 9:643110. doi: 10.3389/fbioe.2021.643110. Coacervation optimally occurs at physiological temperature, however, in vitro coacervation can also occur at lower temperatures depending on experimental conditions and the choice of tropoelastin isoform or derivative (Yeo et al., 2011). doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Natl. 289, 14671477. 276, 3603536042. A. (2001). Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. 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. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). doi: 10.1016/s0934-8832(11)80057-0. doi: 10.1016/j.bbrc.2010.05.013, Elvin, C. M., Carr, A. G., Huson, M. G., Maxwell, J. M., Pearson, R. D., Vuocolo, T., et al. Foster, J. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Molecular modeling of protein materials: case study of elastin. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Biomaterials 127, 4960. Gene 154, 159166. Acta Biomater. Tropoelastins sequence and domain arrangement. Intracellularly, EBP is associated with tropoelastin after the release of the signal peptide and acts as a chaperone to prevent self-aggregation and proteolysis as it transported to the cell membrane, after which EBP is then recycled and serves as a reusable shuttle protein (Hinek et al., 1995). Free energy determinants of secondary structure formation: I. alpha-Helices. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. Mater. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). Chem. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). Elastagens tropoelastin is identical to that present in human tissue, and has many potential clinical applications, including treatment for acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Further to this, the current model of elastin assembly does not account for how long strings or sheets of tropoelastin are capable of forming spherules on a macroscopic scale (Tu et al., 2010). This content is for members only. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Chem. Chemistry 10, 31663176. Biomed. (2011). (1965). doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). 79, 277284. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). 275, 2844928454. II. doi: 10.1016/j.cis.2010.10.003, Yeo, G. C., Tarakanova, A., Baldock, C., Wise, S. G., Buehler, M. J., and Weiss, A. S. (2016). doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Eur. Studies on the reduction of elastin. All rights reserved. Transl. Approximately 90% of tropoelastins lysines undergo modification and/or participate in cross-links, indicating that mature elastin is extensively cross-linked (Kozel et al., 2003; Schmelzer et al., 2019). Matrix Biol. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Cross-linking requires the modification of at least one of the lysine participants by a member of the copper-containing LOX or lysine oxidase-like (LOXL) enzyme families. Direct observation of structure and dynamics during phase separation of an elastomeric protein. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. Biotechnol. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). J. (2018). Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. J. Pathol. Elastin synthesis in arterial smooth muscle cell culture. Communication: coacervation of tropoelastin results in fiber formation. 289, 1005710068. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. Invest. (1989). Dermatol. (2007). U.S.A. 116, 20422051. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). These ordered structures can include -helices and -structures (Vrhovski et al., 1997), which depend on the amino acid content and arrangement of domains (He et al., 2012; Reichheld et al., 2014, 2017; Muiznieks et al., 2015) and the choice of solvent (Reiersen and Rees, 2000; Muiznieks et al., 2015). Cardiovasc. Protein Eng. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). Tropoelastin massively associates during coacervation to form quantized protein spheres. Int. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. This process is reversible and thermodynamically controlled and does not require protein cleavage. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). doi: 10.1016/s0021-9258(19)83613-x, Miao, M., Bellingham, C. M., Stahl, R. J., Sitarz, E. E., Lane, C. J., and Keeley, F. W. (2003). Exp. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Invest. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. J. Mol. Crosslinking [ edit] J. Biochem. 11 Articles, This article is part of the Research Topic, Tropoelastin-Cell Receptor Interactions and Implications for Assembly, https://doi.org/10.3389/fbioe.2021.643110, Creative Commons Attribution License (CC BY). Biophys. Exp. Eur. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. U.S.A. 84, 56805684. J. Hum. Tropoelastin cannot readily be prepared in quantity from natural sources and this has limited research in several important areas including structure/function relationships and fiber assembly. 27, 441450. A single tropoelastin molecule can stretch up to eight times its resting length and has a Youngs modulus (tensile stiffness) of 3 kPa (Baldock et al., 2011) in comparison to elastins extensibility of 150% and stiffness of 1 mPa (Aaron and Gosline, 1981). Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. 28, 432441. Coacervation characteristics of recombinant human tropoelastin. Cell Physiol. A model two-component system for studying the architecture of elastin assembly in vitro. 149, 282289. Stiffness within the context of self-assembly has also been examined with both coarse grained and full-atomistic simulations using polypeptides derived from tropoelastins hydrophobic domains. Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. (2014). doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. 282, 1248412491. 4, 508524. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Proc. A new amino acid from hydrolysates of elastin. The ELN gene provides instructions for making a protein called tropoelastin. The human ELN gene is located on the long arm of chromosome 7q11.2 and comprises of 34 exons nestled between lengthy introns (Indik et al., 1987, 1989; Bashir et al., 1989). Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Fed. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Biosci. Biochimie 86, 173178. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). 98, 416. Biochemistry 45, 99899996. Indeed, cryo-EM was recently reported to have a lower molecular size limit of approximately 50 kDa, however, it has not yet been successfully applied to characterize tropoelastin (Murata and Wolf, 2018). HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). (2012). (2018). 1, 2 Elastogenesis, the process of elastin formation, mainly occurs during the fetal and early neonatal development of organs such as blood vessels, lungs, and skin. 207, 8796. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Meanwhile, modifications to the full-atomistic model have revealed the mechanisms that contribute to aberrant fiber structure (Tarakanova et al., 2018) that have been hypothesized to predispose patients to diseases such as acquired cutis laxa (Hu et al., 2006). 396, 870873. 266, 308314. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. J. Biomol. Elastin is heterogeneously cross-linked. Matrix 12, 156162. 9:eaai7466. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). (2003). 26, 17001709. Tropoelastin was revealed to be an asymmetric molecule with distinct N- and C-terminal regions that are respectively referred to as the "head" and "foot" of the molecule. Trends Biotechnol. Sci. Model. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). 280, 4093940947. Am. Bioeng. doi: 10.1016/j.matbio.2007.05.005, He, D., Miao, M., Sitarz, E. E., Muiznieks, L. D., Reichheld, S., Stahl, R. J., et al. The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). 28, 379382. Allergan markets a portfolio of leading brands and best-in-class products for the central nervous system, eye care, medical aesthetics and dermatology, gastroenterology, womens health, urology and anti-infectivetherapeutic categories. U.S.A. 115, 73387343. Assembly proceeds from a nucleation event and undergoes elongation in a step-wise manner to form a multimer which can occur in a head-to-tail fashion (Wise et al., 2014). Even after being able to produce recombinant tropoelastin at scales suited to characterization studies, traditional techniques have not yet produced an experimentally verified atomistic structure (Martin et al., 1995; Tarakanova and Buehler, 2013).
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