275, 2844928454. Self-healing and thermoreversible rubber from supramolecular assembly. Sci. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. 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. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). Proc. 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). Crucially, these simulations revealed that self-assembly starts with a nucleation event and elongation proceeds via both globular and fibrillar structures (Tarakanova et al., 2019a). Acta Gen. Subj. 3, 4 Elastin has a very low rate of turnover, so it . Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). (2006). Natl. Thus, at lower temperatures, the water surrounding these domains forms ordered, clathrate-like shells that prevent aggregation until the appropriate temperature is reached (Wu and Weiss, 1999; Miao et al., 2003; Dandurand et al., 2015). Fibulin-4 and -5, but not fibulin-2, are associated with tropoelastin deposition in elastin-producing cell culture. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). 276, 4457544580. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. (2005). FEBS J. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. 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). into 200 nm then 12 m spherules, which eventually grow and stabilize into spherules 26 m in diameter (Clarke et al., 2006; Kozel et al., 2006; Tu and Weiss, 2010; Tu et al., 2010). doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). J. Biol. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. 258, 118. Biochem. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. J. Med. Biochimie 86, 173178. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). Biochem. Int. Elastin-like polypeptides as models of intrinsically disordered proteins. Tropoelastin is the soluble precursor of elastin that is secreted as a 60-70-kDa monomer by elastogenic cells such as fibroblasts, lung alveolar cells, chondrocytes, and vascular SMCs [16]. Molecular dynamics modeling of aggregating tropoelastin-derived peptide chains points to the maintenance of a hydrated, disordered, liquid-like state due to the formation of short-lived inter-chain bonds (Rauscher and Pomes, 2017; Reichheld et al., 2020), mostly likely due to the inducement of random coils by PG repeats (vide supra). Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. Matrix Biol. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Int. doi: 10.1002/bip.1981.360200611. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Possible role in nucleated assembly. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Fell muir lecture: collagen fibril formation in vitro and in vivo. Matrix Biol. Rep. 8, 116. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. Mol. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Importantly, the presence of fibrils indicates that the nanostructures formed during initial assembly contribute to the supramolecular structures that arise during both early (spherule) and later (fibril) stages of elastogenesis. Trends Biotechnol. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Eur. 38, 280291. Trends towards maximal association are apparent when each of these parameters is varied. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Allergan's Acquisition of Elastagen. The ELN gene provides instructions for making a protein called tropoelastin. Specific instructions are found in the Directions for Use. Form. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. 396, 870873. The liquid structure of elastin. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. (2019). 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. Computational approaches have gained popularity in recent decades as their methodologies have been refined to provide accurate atomistic scale insights into molecular structure and movement (Tarakanova et al., 2018). Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. (2019b). Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. 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. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. Cell Biol. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). 432, 57365751. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). 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). Micron 32, 185200. Pharm. 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. doi: 10.1016/j.biocel.2008.03.017, Wise, S. G., Yeo, G. C., Hiob, M. A., Rnjak-Kovacina, J., Kaplan, D. L., Ng, M. K., et al. Biol. Macromol. 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. Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. (2017). J. Biol. Chem. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Figure 1. Collapse Section. Nature 437, 9991002. Chemistry 10, 31663176. (1987). 410, 317323. Biopolymers 103, 563573. 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). (2016). 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. (2009). Hydrophobic domains of human tropoelastin interact in a context-dependent manner. Colloid Interface Sci. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Proc. 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. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer 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. We are making enrolling in text alerts easier than ever. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. It is likely that, as a general rule, integrin binding to tropoelastin is mediated via GAGs, which is facilitated by the repetition of tropoelastins primary sequence and the surface exposure of positively charged similar domains (Lee et al., 2017; Bochicchio et al., 2021). (2018). 289, 489492. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. 27, 441450. Mater. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Elastagen's 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. Chem. Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. Med. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Front. Biochemistry 36, 84138421. 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). Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. 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). Cell Biol. Ltd., which was sold to Allergan, now a division of AbbVie. (2007). Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Matrix Biol. Exp. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. (2008). The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. 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. 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. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. 278, 1849118498. (1995). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. 284, 22162230. Invest. 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). Baul, U., Bley, M., and Dzubiella, J. 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. Elastagen's revolutionary recombinant human tropoelastin, is identical to that present in human tissue and has many clinical applications, including effective breakthrough treatments for acne. Biochemistry 45, 95189530. 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). (2014). 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). Res. 25, 10231029. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. Biotechnol., 25 February 2021, View all Elastogenesis is the term that collectively describes the hierarchical process of elastic fiber formation, and is comprised of distinct phases: tropoelastin synthesis, coacervation, cross-linking, and deposition. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). J. Biol. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Chem. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance. J. Biochem. 84, 6880. For more information, visit Allergans website atwww.Allergan.com. Biochemistry 52, 77317741. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Natl. J. Mol. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. 4, 508524. 41, 494497. 589(19 Pt A), 24772486. U.S.A. 115, 73387343. Chem. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. 98, 416. FEBS J. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Exp. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Biopolymers [Epub ahead of print]. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. Biochemistry of tropoelastin. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. 79, 277284. 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. (2015). Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Sci. Arch. Cytochem. This temperature is also known as the transition temperature. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 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. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Nat. 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. For this injection, the researchers used a new . Calorim. FASEB J. Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. All rights reserved. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. 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). Elastin is heterogeneously cross-linked. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Furthermore, tropoelastins hydrophobic and cross-linking domains are arranged in alternating patterns throughout the majority of the molecule, giving rise to both inter- and intra-domain level repetition. Biophys. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). A. Implications for tissue specificity and durability of elastic tissue. Am. An electron microscopic study. (2013). Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Matrix Biol. By probing mutations in computational studies that resolve the atomistic structure of the molecule, the deduction of mechanisms associated with changes to functional roles of specific domains has become feasible, and a connection between local structures and biological performance can be established (Figure 2; Tarakanova et al., 2018). Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Figure 3. (2018). Furthermore, the SAXS/SANS structure has been mapped to an elastic network model with tunable stiffness to probe the role of tropoelastins flexibility in fiber assembly (Yeo et al., 2016). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. J. Biochem. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Chem. 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.