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. This deduction has been corroborated by the observation that tropoelastin with multiple allysine modifications displays conformational sampling comparable to that of the wild-type molecule, suggesting it is more likely to readily participate in self-assembly. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Gene 154, 159166. Domain 36 of tropoelastin in elastic fiber formation. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. 58, 270277. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Indeed, cryo-EM was recently reported to have a lower molecular size limit of approximately 50 kDa, however, it has not yet been successfully applied to characterize tropoelastin (Murata and Wolf, 2018). doi: 10.1021/bi981641y, Kozel, B. 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. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). (2017). Matrix Biol. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Domains 12 to 16 of tropoelastin promote cell attachment and spreading 11 Articles, This article is part of the Research Topic, Tropoelastin-Cell Receptor Interactions and Implications for Assembly, https://doi.org/10.3389/fbioe.2021.643110, Creative Commons Attribution License (CC BY). Biochemistry 45, 99899996. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). 26, 125135. Pharmacol. Matrix 12, 156162. Acad. Model. We are making enrolling in text alerts easier than ever. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. 276, 4457544580. 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). Chem. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. (1988). Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. Acad. 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. Novel Recombinant Tropoelastin Implants Restore Skin Extracellular Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. 252, 351365. Pathol. 282, 1248412491. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas 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). Tropoelastins domains each arise from single exons of the ELN gene. Natl. J. Hum. The liquid structure of elastin. Tropoelastin: a versatile, bioactive assembly module - PubMed (1965). Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). *Correspondence: Anthony S. Weiss, tony.weiss@sydney.edu.au, These authors have contributed equally to this work, Fibrous Assemblies: From Synthesis and Nanostructure Characterization to Materials Development and Application, Front. Med. Biol. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Biopolymers 20, 12471260. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). 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. eLife 6:e26526. AW gratefully acknowledges NHMRC funding (Ref: 1195827). Chem. doi: 10.1016/j.matbio.2006.08.258, Clarke, A. W., Arnspang, E. C., Mithieux, S. M., Korkmaz, E., Braet, F., and Weiss, A. S. (2006). Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Acad. Dyn. Stages of hierarchical assembly of elastic fibers. Dermatol. LOX and LOXL convert the -amino group of lysine to -aminoadipic acid -semialdehyde (allysine) (Schmelzer et al., 2019), which spontaneously undergo either a Schiff base reaction with a lysine, or two allysines crosslink through aldol condensation, to give rise to bifunctional crosslinks (Franzblau et al., 1969; Lent et al., 1969). 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). EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Eur. 589(19 Pt A), 24772486. Baul, U., Bley, M., and Dzubiella, J. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Primary structure of porcine tropoelastin. Exp. 410, 317323. Studies on the reduction of elastin. Cell Biol. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. (2005). I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. doi: 10.1038/nature04085. 258, 118. Biol. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. II. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Patient Homepage | Accredo Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. Exp. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. 33, 54685481. 289, 1005710068. Tropoelastin - PubMed The last 17 amino acid residues of the C-terminus of domain 36 are also implicated in HS interactions; the last four residues are Arg-Lys-Arg-Lys and are positively charged at physiological pH which provides a charged cluster capable of binding negatively charged HS (Broekelmann et al., 2005). For more information, visit Elastagens website atwww.elastagen.com. The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). 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. 120, 419426. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). Allergan to acquire University of Sydney spinoff Elastagen Natl. 286, 35943610. 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). 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]. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). All rights reserved. Coacervation involves the agglomeration of protein molecules, which is an . 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. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. Attempts to characterize tropoelastins structure have seen a gradual shift from the belief that tropoelastins domains have fixed structures, to understanding that the majority of its domains are capable of transitioning between random coils and transient ordered structures. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Tropoelastins sequence and domain arrangement. Natl. 249, 997998. Poly (Val-Gly-Gly-Leu-Gly). Chem. Parameter, Testing, and Method. J. Biochem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Acad. 26, 115124. To get started with texting, you will need: Your phone number 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). 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). 281, 2375723765. Matrix Biol. J. Biol. Exp. Dermatol. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. The coacervate is made insoluble by irreversible crosslinking. 10, 441454. doi: 10.1073/pnas.1014280108. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Imaging 11:e007303. Natl. 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. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. Allergan Snaps Up Sydney Biotech for Upfront Payment of US $95M The N-terminal head caps an extended coil region that consists of domains 218. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. 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). 43, 131138. More recently, it has been demonstrated that KA domains consist of random coil content prior to self-assembly and become more ordered as molecules aggregate, marrying the observations discussed above into a cohesive model within the context of assembly and the requirements of higher-order structures (Reichheld et al., 2014). How to Get LONGER Eyelashes - Guaranteed | NULASTIN 29, 152159. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. Biotechnol. Matrix Biol. Cell Biol. Moreover, fibulins are essential for elastic fiber directionality, as fibroblasts with fibulin-4 and -5 knockdowns generate poorly formed elastic fibers (Yamauchi et al., 2010), and fibulin-4 / mice display aberrant, poorly cross-linked, and non-fibrous elastin (McLaughlin et al., 2006). Powered by Madgex Job Board Software. Specific instructions are found in the Directions for Use. J. Biol. (1983). 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.. Shape of tropoelastin, the highly extensible protein that - PNAS doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Trends towards maximal association are apparent when each of these parameters is varied. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. 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. Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Cell Biol. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Eur. 293, 1510715119. Chemistry 10, 31663176. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). 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. Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. (2012). Fluor: Q4 Earnings Snapshot. Biopolymers 29, 16991706. 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). Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Eng. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Front. Indeed, studies examining the consequences of domain insertions and deletions note changes in the intrinsic functionality of tropoelastin, corroborating the hypothesis that domain insertions and deletions result in altered tissue mechanics (Jensen et al., 2000; Kozel et al., 2003; Yeo et al., 2016; Miao et al., 2017). Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 278, 1849118498. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Molecular modeling of protein materials: case study of elastin. Fabricating organized elastin in vascular grafts. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Direct observation of structure and dynamics during phase separation of an elastomeric protein. 84, 6880. Proc. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. (2015). (1995). Sci. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. Matrix Biol. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. February 14, 2018 Michael Patrini. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . J. Biomol. (2016). 85, 593605. It has become increasingly evident that tropoelastins sequence, structure and subsequent functionality are in a delicate balance; thus, perturbations to tropoelastins sequence can have far-reaching consequences for self-assembly and the resultant architecture of elastic fibers. Allergan announced that it would be accessing Elastagen's next generation Juvederm dermal filler injectable portfolio, which will now also boast its "key 'youth protein' tropoelastin". Mol. (2011). Arch. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Biol. FEBS J. J. Biol. (1989). 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. Chem. AW is the Scientific Founder of Elastagen Pty. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). 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). Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. 280, 4093940947. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Figure 3. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Mater. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. Stiffness within the context of self-assembly has also been examined with both coarse grained and full-atomistic simulations using polypeptides derived from tropoelastins hydrophobic domains. Elastin is one of the most abundant proteins in your body. Proc. A model two-component system for studying the architecture of elastin assembly in vitro. Biotechnol., 25 February 2021, View all doi: 10.1016/s0934-8832(11)80057-0. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. 270, 1777817783. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Scientists find way to heal scars left behind by heart attacks Tropoelastin | Circulation: Cardiovascular Imaging Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. This process is reversible and thermodynamically controlled and does not require protein cleavage. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. 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. Tropoelastin is a flexible molecule that retains its canonical shape. Struct. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Natl. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. (1973). Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. 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. Matrix Biol. (2014). US8974803B2 - Injectable biomaterials - Google Patents

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