21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. 79, 277284. Rep. 8, 116. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . DEERFIELD, IL - Caterpillar Inc. (NYSE: CAT) today announced it will move its global headquarters to the company's existing office in Irving, Texas, from its current location in Deerfield, Illinois. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Macromol. Biol. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. doi: 10.7554/eLife.26526. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Adv. Biochim. The study is designed to evaluate the efficacy of two formulations of a cross-linked tropoelastin matrix given the product codes ELAPR002f (collectively referred to as ELAPR or ELAPR002) for the treatment of rolling atrophic acne scars when administered as intradermal implants. Chem. Four days after a heart attack, purified tropoelastin was injected into the heart. The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). Domain 36 of tropoelastin in elastic fiber formation. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. Natl. Elastin is one of the most abundant proteins in your body. Natl. Sci. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. (2018). The cross-linking domains are enriched for either Lys-Pro (KP) or Lys-Ala (KA) motifs and form cross-links that link growing tropoelastin chains during elastogenesis; note that exon 6 encodes a KA domain. Acta Gen. Subj. U.S.A. 110, 28522857. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Foster, J. Genet. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. J. Biochem. (2019a). Ann. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. I thank the Elastagen team for their hard work and dedication in developing our innovative tropoelastin product pipeline and look forward to working with Allergan to take these products to market., Commenting on the transaction, Elastagens founding scientist Prof Anthony Weiss added:Our technology has come a long way from the lab bench at the University of Sydney towards developing products for patients around the world. The presence of tropoelastin spherules fusing to fibrils has been noted in native tissue, demonstrating marked similarities between in vitro and in vivo coacervation (Haust et al., 1965; Albert, 1972; Kozel et al., 2006). 282, 1248412491. The reduction in solvent accessible surface area of the mutant molecules suggests that the underlying mechanism for their altered self-assembly properties observed in experiments is due to less exposure of the appropriate hydrophobic domains required for coacervation. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. Chem. Most organisms contain one copy of ELN, other than teleosts and amphibians which notably possess two distinct types of ELN genes (He et al., 2007; Miao et al., 2007, 2009). doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Domains 2736 make up tropoelastins foot, which are labeled as such due to their spatial arrangement, forming an almost claw-like component of the molecule. Mol. By leveraging the advantages of computational models, such as elastic network models, full-atomistic models and coarse grained models, as depicted in Figure 2, the correlation between the structure, motions, and the functionality of tropoelastin have recently been explored in depth (Yeo et al., 2016; Tarakanova et al., 2018, 2019a). Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. Provides infrastructure for further development and following approval to commercialize Elastagens products, SYDNEY February 7th: Elastagen Pty Limited, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced that it has entered into a definitive agreement under which Allergan, a leading global biopharmaceutical company, has agreed to acquire Elastagen for an upfront payment of US$95M plus contingent, commercial payments.. All authors contributed to writing and editing the review. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Proc. Computational smart polymer design based on elastin protein mutability. (2020). The conserved C-terminus is an area of the molecule of particular biological importance in that it is required for both incorporation into elastin and for cellular interactions. 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. (2018). Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Elastagen's technology is based on human tropoelastin . The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). doi: 10.1038/nature04085. 250, 9298. Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. Am. Biochem. Matrix 12, 156162. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 289, 489492. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Elastin: molecular description and function. (1973). In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. Tropoelastin: a novel marker for plaque progression and instability. Mater. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Biopolymers 107:e23007. (2013). For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Matrix Biol. 29, 152159. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Biopolymers 20, 12471260. No use, distribution or reproduction is permitted which does not comply with these terms. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Chem. Fibrillin-1 interactions with heparin. Sci. Cell Biol. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Tropoelastin is typically used as a thin coating on tissue culture surfaces. J. Biochem. Cell Biol. 278, 1849118498. Biopolymers [Epub ahead of print]. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. 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). The authors wrote and submitted this manuscript in response to an invitation by the Editor. Chemistry 10, 31663176. 10, 441454. Elastin is a critical skin protein consisting of crosslinked tropoelastin. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Arch. U.S.A. 115, 73387343. Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. Ltd., which was sold to Allergan, now a division of AbbVie. 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. Further down the molecule, the cell-interactive C-terminus was noted to be highly flexible, indicating that high conformational sampling could be conducive to tropoelastins interactions between cell-surface receptors and elastic fiber-associated proteins. Gene 154, 159166. Communication: coacervation of tropoelastin results in fiber formation. Allergan Plc, a $15.9b provider of medical aesthetics, biosimilars, and over-the-counter pharmaceutical products will acquire Elastagen Pty Ltd., a provider of advanced tissue repair platform based on tropoelastin (gives tissue its elasticity) for $95m.The acquisition adds proprietary injectable products to Allergan's existing portfolio. 26, 115124. (2019b). A., Torres, A. R., Alvarez, V. L., and Janata, J. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Matrix Biol. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. Human ELN gives rise to a broad variety of splice isoforms, with alternative splicing being observed with exons 22, 23, 24, 26A, 32, and 33 (Fazio et al., 1988; Parks et al., 1992) that result in 13 known human isoforms of the mature tropoelastin protein (Reichheld et al., 2019). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. Acta Biomater. 396, 870873. This acquisition and the development of a next generation of injectables based on this technology will ensure Allergan offers innovative filler products for years to come., Robert Daniels, Elastagen CEO, noted: Partnering with Allergan, a leader in medical aesthetics, is incredibly exciting. Today Biol. Thus, computational approaches can be considered as important means to complement wet bench experiments. The conversion of a single lysine to an allysine results in structural stabilization, which may serve as a checkpoint during self-assembly to ensure that molecules incapable of forming multiple cross-links are not incorporated into the growing chain. (2015). Chem. Elastogenesis in human aorta: an electron microscopic study. Cell Biol. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Free energy determinants of secondary structure formation: I. alpha-Helices. J. Biol. 281, 2375723765. 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. Cell Biol. 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). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Tropoelastins hydrophobic domains are predominantly responsible for the random coil content of the monomer, and are the result of the unique pairing of proline and glycine pairs that are interspersed throughout the majority of hydrophobic domains (Rauscher and Pomes, 2017). Fibrillin-1 and -2 also interact with proteoglycans (Tiedemann et al., 2001), which coupled with tropoelastin/GAG interactions provide a pathway to the formation of elastic fibers. Dyn. doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. 9:643110. doi: 10.3389/fbioe.2021.643110. II. Cytochem. 276, 4457544580. Thus, elastin is responsible, in great part, for the properties of elastic fibers. Biol. (2006). Simul. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. Engineering a highly elastic human protein-based sealant for surgical applications. Tropoelastin massively associates during coacervation to form quantized protein spheres. Biophys. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Although there is no 3D structure for porcine tropoelastin, porcine tropoelastin differs from that of humans (Sandberg et al., 1977), leaving it unclear as to whether these domains align as expected in human tissue. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Acad. Front. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). doi: 10.1002/jcp.20546, Kozel, B. 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: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). (2006). Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Acta 303, 363369. Med. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). (2007). Sci. The isoform-function theory is further reinforced by the presence of two different ELN genes within teleosts that are differentially expressed both spatially and temporally during development (Miao et al., 2007). A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. 258, 118. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. The full-atomistic model of tropoelastin was developed based on replica exchange molecular dynamics (REMD) simulations, an accelerated sampling method for molecular dynamics (Tarakanova et al., 2018). Interactions with these integrins on the surface of mesenchymal stem cells, either through surface bound or as soluble tropoelastin, promote MSC proliferation and phenotypic maintenance via FAK and PKB/AKT (Yeo and Weiss, 2019). Elastin synthesis during perinatal lung development in the rat. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). (2001). doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). 13, 739743. Structural changes and facilitated association of tropoelastin. Chem. A model two-component system for studying the architecture of elastin assembly in vitro. 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). We are very interested in the blend of biochemistry and cell biology, as well as the tissue engineering and regenerative medicine opportunities provided by this amazing elastic protein. (2003). (1981). Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Biosynthesis and nature of elastin structures. Biol. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). J. Biol. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Acad. doi: 10.1016/j.biomaterials.2017.04.050, Keywords: elastin, elastic fibers, tropoelastin, computational modeling, assembly, Citation: Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A and Weiss AS (2021) Tropoelastin and Elastin Assembly.
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