tropoelastin allergan

tropoelastin allergan

4, 508524. Sci. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. 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. 410, 317323. 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. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Biopolymers 107:e23007. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). 258, 118. (2006). Exp. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). 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). Adv. doi: 10.1016/s0934-8832(11)80057-0. Biochemistry 52, 77317741. 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). The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). February 14, 2018 Michael Patrini. Adv. Biol. J. Biol. 85, 593605. 278, 1849118498. (2015). (2018). It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. 589(19 Pt A), 24772486. Figure 2. Acad. Nat. 38, 280291. 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). 432, 57365751. Biopolymers [Epub ahead of print]. 22, 109121. Trends Biotechnol. A., Torres, A. R., Alvarez, V. L., and Janata, J. Eng. FASEB J. 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. Mater. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Lysinonorleucine. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. Biochemistry 45, 99899996. Interestingly, the location and orientation of different domains that contacted each other during self-assembly was noted to be heterogeneous, resulting in head-to-head, tail-to-tail, head-to-tail, and lateral interactions (Tarakanova et al., 2019a). doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). Front. Natl. 276, 4457544580. Chem. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. 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.. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Biochem. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. 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). Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). Domain 26 of tropoelastin plays a dominant role in association by coacervation. Possible role in nucleated assembly. Pharmacol. Proc. Form. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. doi: 10.7554/eLife.26526. A., Gray, W. R., and Franzblau, C. (1973). doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). doi: 10.1038/nature04085. 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). Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Acta Gen. Subj. Eng. Coacervation characteristics of recombinant human tropoelastin. Biosynthesis and nature of elastin structures. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). 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. 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. EBP plays two roles in the assembly of elastin. Biophys. 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. (2003). Micron 41, 268272. J. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Matrix Biol. Structural changes and facilitated association of tropoelastin. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. 276, 3603536042. Dyn. (2014). (2011). doi: 10.1073/pnas.1014280108. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. Such models could be used in conjunction with the full molecular model of tropoelastin to examine the self-assembly of discrete regions to understand the impacts of amino acid substitutions in disease. (1965). Cell Res. Sci. 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). doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. (1981). Specific instructions are found in the Directions for Use. (2020). 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). doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. A. Matrix Biol. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). N. Y. Acad. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Biol. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Modeling has been verified using wet-bench methodologies, forming a robust suite of complementary methodologies that will undoubtedly become more prevalent for exploring the assembly of biological fibers over time. 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. Biol. 280, 4093940947. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Chem. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Biol. 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. J. Pathol. For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. (2018). doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). 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). Coacervation involves the agglomeration of protein molecules, which is an . Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). (2015). doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). 207, 8796. 289, 489492. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. Cell Biol. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. While tropoelastin is a flexible molecule, a combination of optical and structural analyses has defined key regions of the molecule that directly contribute to the elastomeric properties and control the cell interactions of the protein. 3, 4 Elastin has a very low rate of turnover, so it . Primary structure of porcine tropoelastin. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Matrix Biol. . doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. J. Biol. Tropoelastin is a flexible molecule that retains its canonical shape. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Biophys. 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. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Elastin-like polypeptides as models of intrinsically disordered proteins. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 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. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Fabricating organized elastin in vascular grafts. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). J. Biol. Arch. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. 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). 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). Coacervation of tropoelastin. 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. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Natl. Biochemistry 8, 28332837. Med. 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,". Synthesis and properties of crosslinked recombinant pro-resilin. The resultant bending motion rather than scissors-twist motion that stemmed from this stabilization highlights the mutants diminished flexibility as a key driver of impaired fiber assembly in cutis laxa (Tarakanova et al., 2018). 58, 270277. Chemistry 10, 31663176. Chem. Sci. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Elastagen's technology is based on human tropoelastin . Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. 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. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. 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. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. 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 On the cell surface, EBP forms a complex with protective protein/cathepsin A (PPCA) and neuraminidase-1 (Neu-1), giving rise to the ERC (Duca et al., 2007). 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). Additionally, coarse-graining the full-atomistic model has allowed for the examination of mesoscale tropoelastin assembly and, in particular, deciphered the orientation of tropoelastin molecules that occurs during early stage assembly (inset image) (Tarakanova et al., 2019a). Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. Cytochem. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. (1995). Pediatr. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Rep. 8, 116. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). J. Biol. Mater. Cell Biol. J. Struct. Proc. Acad. J. All rights reserved. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Parameter, Testing, and Method. (1989). doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). (1995). The N-terminal head caps an extended coil region that consists of domains 2-18. The lysines of domain 15 and 17 are believed to play key roles in this interaction. U.S.A. 84, 56805684. Sci. Genet. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. FEBS J. (2017). I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. J. Biol. 150, 154162. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. 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). Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. 275, 2844928454. 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). A., Starcher, B. C., and Urry, D. W. (1974). Tropoelastin is typically used as a thin coating on tissue culture surfaces. Tropoelastin: a novel marker for plaque progression and instability. (2007). 2:e1501145. Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). Engineering a highly elastic human protein-based sealant for surgical applications. Matrix Biol. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Exp. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Earnings, adjusted for non-recurring costs, came . 33, 54685481. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). J. Med. 250, 9298. 396, 870873. 149, 282289. Acta 303, 363369. 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]. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Today Biol. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). Protein Eng. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. 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. Int. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). 84, 6880. Furthermore, as integrins are involved in the remodeling of the ECM (Bonnans et al., 2014), this is consistent with a model where the tropoelastin-integrin interaction forms part of the wound repair process. 281, 2375723765. Modulative effects are also observed within full length tropoelastin, where disruptions to domain 26 diminish self-assembly (Jensen et al., 2000), highlighting the context of primary sequence on higher order structures. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Biol. Cross-linking domains can be subdivided into KP or KA domains, which denote the amino acids (proline or alanine, respectively) that are adjacent to the lysines (Figure 1). Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . Ann. The liquid structure of elastin. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . J. Mol. (2015). This temperature is also known as the transition temperature. (2005). 15, 786801. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. Cell. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. Biopolymers 20, 12471260. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. Four days after a heart attack, purified tropoelastin was injected into the heart. Communication: coacervation of tropoelastin results in fiber formation. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. Int. 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). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. FEBS J. Conformational transitions of the cross-linking domains of elastin during self-assembly. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Gene 154, 159166. Colloid Interface Sci. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Res. Acad. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Genet. doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. 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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