Biochemistry 42, 1334713362. Fluor: Q4 Earnings Snapshot. (2019). doi: 10.1021/bi981641y, Kozel, B. Elastin is one of the most abundant proteins in your body. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). doi: 10.1002/bip.1981.360200611. Tropoelastins sequence and domain arrangement. Foster, J. (2019). A. Biochem. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). 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. Chem. Biol. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. Elastin synthesis in arterial smooth muscle cell culture. Acad. Gene 154, 159166. Biotechnol. Med. Genet. 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. Biopolymers 29, 16991706. N. Y. Acad. 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). Pharm. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Biomacromolecules 18, 599609. 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. Adv. Aaron, B., and Gosline, J. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). Acta 303, 363369. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). (2018). Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. Acad. J. Biochem. J. Biol. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). Figure 3. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Banded fibers in tropoelastin coacervates at physiological temperatures. 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. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Tropoelastin is a low complexity protein on both primary and secondary sequence levels. The smallest amino acid, glycine is known to promote flexibility within local structures due to lack of steric hindrance, whereas prolines restrictive sidechain inhibits conformational sampling and disrupts the formation of prolonged secondary structures (Roberts et al., 2015). Characterization of the complete human elastin gene. 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). (2006). Implications for tissue specificity and durability of elastic tissue. 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. 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. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. All rights reserved. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Anal. Earnings, adjusted for non-recurring costs, came . The ELN gene provides instructions for making a protein called tropoelastin. Chem. Targeted modulation of tropoelastin structure and assembly. 43, 131138. J. Biol. Mater. Isolation and characterization of crosslinked peptides from elastin. Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). Tropoelastin undergoes minimal energy loss during extension, similar to other polymers such as rubber and resilin (Elvin et al., 2005; Cordier et al., 2008; Baldock et al., 2011). J. doi: 10.1073/pnas.1014280108. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. Fabricating organized elastin in vascular grafts. The amino acid sequence of domain 36 is unique; furthermore, its sequence confers a positively charged C-terminus comprising lysines between positively charged arginines, forming a RKRK sequence (Vrhovski et al., 1997). In contrast, higher temperatures allow the breaking of the hydrogen bonds of the ordered water, dissipating the clathrate shells and permitting the association of the hydrophobic domains (Yeo et al., 2011). Sci. 284, 22162230. Lyophilized Powder. Proc. Chemistry 10, 31663176. FASEB J. The elasticity of organs and tissues in vertebrates is due to the presence of elastin, and an insoluble protein whose soluble monomer, tropoelastin, is enzymatically cross-linked through -amino groups of lysine residues. 29, 152159. 266, 308314. 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). Allergan is an industry leader in Open Science,a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Nature 437, 9991002. (1989). doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. 38, 280291. 98, 416. Synthesis and structural studies of a pentapeptide sequence of elastin. 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.. Biochemistry 8, 28372845. (2013). Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. A., Torres, A. R., Alvarez, V. L., and Janata, J. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). (1981). The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Domain 36 of tropoelastin in elastic fiber formation. J. Mol. Int. In addition to interacting with tropoelastin, fibulin-4 and -5 are capable of also binding LOX and fibrillin-1 and, thus, have key roles in facilitating elastogenesis (Hinderer et al., 2015). Med. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. 28, 432441. . The first successful experiments to define the 3D envelope of tropoelastin utilized small angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) (Baldock et al., 2011). Int. Chem. (2017). Acta 761, 1722. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. doi: 10.1002/jcp.20546, Kozel, B. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. J. Biol. Biopolymers 107:e23007. This suggests the ERCs primary signal pathways are involved in wound recognition through fragments of elastin, where EDPs are formed as a result of elastic tissue damage. 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: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). J. Exp. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Transl. Adv. Biochemistry 8, 28332837. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Eur. 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). 26, 125135. (1995). Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Engineering a highly elastic human protein-based sealant for surgical applications. Colloid Interface Sci. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. Tropoelastin: a versatile, bioactive assembly module. Rev. 9:eaai7466. U.S.A. 110, 28522857. doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. Proc. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Baul, U., Bley, M., and Dzubiella, J. Natl. 260, 32553258. (2005). 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). 69, 89102. (1965). With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. The hydrophobic domains contain repetitions and variations of Val-Pro-Gly-Val-Gly motifs (Figure 1), resulting in the aforementioned low complexity of sequence (Foster et al., 1973; Gray et al., 1973). doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. 167, 94103. Matrix Biol. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. (2020). The liquid structure of elastin. We are making enrolling in text alerts easier than ever. 250, 9298. The alignment of the tropoelastin aggregates . Tropoelastin massively associates during coacervation to form quantized protein spheres. Tropoelastin, the raw material used to create 'MeTro' elastic surgical glue developed with the University of Sydney, has been found to encourage stem cell growth - with the potential to ultimately help the body repair itself. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). (1973). The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures.
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