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280, 4093940947. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Am. Chem. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). For more information, visit Allergans website atwww.Allergan.com. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). 16,17 We have previously shown that monomeric TE is utilized as a substrate by dermal fibroblasts in the formation of elastin fibroblasts in vitro, where (2006). Elastagen has received investment from an international syndicate of venture groups including AmorePacific Ventures, Brandon Capital, Cell Innovation Partners, Cicada Innovations, GBS Ventures, Korea Investment Partners and the Wellcome Trust. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. A., and Rucker, R. B. 432, 57365751. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. 249, 997998. Foster, J. 410, 317323. The majority of tropoelastin synthesis occurs during perinatal development (Myers et al., 1983; Noguchi et al., 1990), however, synthesis may be triggered in response to tissue damage (Parks et al., 1992) or during diseases such as atherosclerosis (Phinikaridou et al., 2018). J. Biol. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). The smooth muscle cell. Acta 303, 363369. 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. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Int. Free energy determinants of secondary structure formation: I. alpha-Helices. Sci. Chem. Molecular model for elastin structure and function. Rep. 8, 116. Computational smart polymer design based on elastin protein mutability. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Tropoelastin massively associates during coacervation to form quantized protein spheres. 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. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. 27, 441450. Natl. Aaron, B., and Gosline, J. III. (2008). Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. . J. Invest. J. Exp. J. Biol. 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. 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. The liquid structure of elastin. (2011). Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. A. Coacervation involves the agglomeration of protein molecules, which is an . J. Biomol. 26, 125135. Arch. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. J. Biol. 26, 524540. Biochem. Tropoelastin #5052. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. Acad. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Biopolymers 20, 12471260. Proc. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Characterization of the complete human elastin gene. Elastin-like polypeptides as models of intrinsically disordered proteins. J. Natl. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 7:32. doi: 10.3389/fphar.2016.00032, Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M. P., Jowitt, T. A., Marchand, M. F., et al. However, higher resolution data were required to map out its elusive properties and performance within a hierarchical assembly (Tarakanova et al., 2018; Ozsvar et al., 2019). 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. J. Biochem. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. Tropoelastin has 2 alternating domains: (1) hydrophilic, cross-linked, domains rich in Lys and Ala; and (2) hydrophobic domains (responsible for elasticity) rich in Val, Pro, and Gly, which often occur in repeats of VPGVG or VGGVG. Pathol. Genet. (2014). 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. The most crucial of these properties is the ability to undergo many stretch-recoil cycles whilst maintaining the structural and functional integrity of elastic tissues over an organisms lifetime. The lysines of domain 15 and 17 are believed to play key roles in this interaction. 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. FEBS Lett. This phenomenon is supported by in vitro peptide studies, which note that increasing the space between PG motifs or removing prolines results in more ordered structures (Rauscher et al., 2006). doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. Biomed. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Ltd., which was sold to Allergan, now a division of AbbVie. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. Lab. Isolation and characterization of crosslinked peptides from elastin. Eur. Fed. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. U.S.A. 110, 28522857. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. B., Broekelmann, T. J., et al. (1989). Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. All authors contributed to writing and editing the review. (2021). (1983). Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). 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). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Biotechnol., 25 February 2021, View all U.S.A. 109, 28782883. Allergan's Acquisition of Elastagen. Model. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Elastagens revolutionary recombinant human tropoelastin, is identical to that present in human tissue and has many clinical applications, including effective breakthrough treatments for acne scars, stretch marks, aesthetic skin repair and wound repair. Acad. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. Elastases can be in the form of serine- (e.g., Ela-2), cysteine- (e.g., cathepsin I), or matrix metalloproteinases (MMP-2, -7, -9, and -12), and bioactive peptides include the VGVAPG peptide. Primary structure of porcine tropoelastin. A model two-component system for studying the architecture of elastin assembly in vitro. 293, 1510715119. Fabricating organized elastin in vascular grafts. 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). Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. 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. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. 1862, 324334. 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). Non-polar residues are a major contributor to protein folding, as their unfavorable interactions with water drive them to bury into the protein core, however, as tropoelastin is comprised of numerous hydrophobic domains, it has been demonstrated that many of these domains will be at least partially solvent exposed (Dyksterhuis et al., 2007). Its estimated half-life of 70 years (Shapiro et al., 1991) is due to its extensive cross-linking and high hydrophobicity, which render it resistant to degradation (Vrhovski and Weiss, 1998; Schrader et al., 2018; Hedtke et al., 2019). Developing elastic tissue. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Elastin synthesis and fiber assembly. Combinations of these two amino acids result in domains that undergo rapid conformational sampling (Rauscher and Pomes, 2017), which, if perturbed toward a conformation that gravitate toward stability, will assemble into highly ordered amyloid-like fibrils that are not elastomeric (Rauscher et al., 2006; Roberts et al., 2015). Due to the lack of a full-atomistic structure, a number of elastin derivatives, including isolated tropoelastin domains (Toonkool et al., 2001; Mackay et al., 2005; Dyksterhuis et al., 2007; Dyksterhuis and Weiss, 2010) and synthetic elastin-derived peptides (EDPs) (Luan et al., 1990; Tamburro et al., 1992; Kentsis and Sosnick, 1998; Kumashiro et al., 2006; Reichheld et al., 2014, 2017; Muiznieks et al., 2015; MacEwan et al., 2017; Tarakanova et al., 2017) have been studied to understand tropoelastins domain level properties. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Natl. 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). J. Med. Biol. Commun. Although alanine tracts within other proteins are predisposed to -helix formation (Yang and Honig, 1995; Avbelj, 2000), high helical content within tropoelastins KA domains was primarily demonstrated to persist in solvents that stabilize secondary structure, such as trifluoroethanol, rather than aqueous solution (Luo and Baldwin, 1997; Tamburro et al., 2006). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Closer to the base of the molecule, the flexible hinge region between domains 21 and 23 presented with a scissors-like bending, which is now believed to contribute to elasticity and multimeric assembly through enhanced conformational space sampling (Tarakanova et al., 2019b). Trends towards maximal association are apparent when each of these parameters is varied. 79, 277284. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). U.S.A. 112, E4408E4415. Exp. (2012). 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. 3, 28322844. Micron 41, 268272. 37, 698702. J. Biol. Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. U.S.A. 84, 56805684. (2016). Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Cell Res. 252, 351365. 260, 32553258. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. Elastin synthesis during perinatal lung development in the rat. 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). 281, 2375723765. Med. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Matrix Biol. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. It was first hypothesized that tropoelastin assembles in a head-to-tail manner similar to that of other ECM proteins such as collagen, which assembles into fibrils that subsequently associate laterally to form sheets and thicker fibers (Kadler, 2017). The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. Dermatol. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. doi: 10.1016/s0934-8832(11)80057-0. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. A., Starcher, B. C., and Urry, D. W. (1974). IRVING, Texas (AP) IRVING, Texas (AP) Fluor Corp. (FLR) on Tuesday reported fourth-quarter net income of $9 million, after reporting a loss in the same period a year earlier. The narrow specificity to v3 and 53 may also be beneficial compared with other ECM adhesion molecules such as fibronectin (which can adhere to up to 20 types of integrin) which may compete with and modulate binding to tropoelastin, and deliver opposing effects on cell proliferation. FASEB J. Sci. 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. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Cellular expression of tropoelastin mRNA splice variants. Chem. Elastagen Pty Ltd, 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 plc, a leading global biopharmaceutical company, has agreed to acquire Elastagen. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. (2018). J. Biol. U.S.A. 115, 73387343. Allergans success is powered by our global colleagues commitment to being Bold for Life. 9:eaai7466. (2019b). doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Similarly, a mutation model associated with cutis laxa, or loose skin disease (Hu et al., 2006), was found to exhibit higher stability compared with the wild-type molecule due to the increased longevity of its salt bridges (Hu et al., 2006; Tarakanova et al., 2018). doi: 10.1021/bi981641y, Kozel, B. (2019). Biol. 624, 137146. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Int. Cell Physiol. Mol. Hogan Lovells represented Elastagen Pty Ltd. on the deal. Chem. Natl. 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). 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). 207, 8796. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Package Size. Synthesis and properties of crosslinked recombinant pro-resilin. Fell muir lecture: collagen fibril formation in vitro and in vivo. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. Modeling utilizing tropoelastin derivatives has demonstrated that structural compaction into both coils and globules occurs above the transition temperature of self-assembly, which may assist in explaining the anisotropic nature of mature elastin (Baul et al., 2020). Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. (2006). doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin.