Allergan Highlights Key Growth Drivers for Medical Aesthetics - PR Newswire Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Circ. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. Tropoelastins C-terminal domain 36 (yellow) does not fall into either category as it contains a distinct sequence capped with a Gly-Arg-Lys-Arg-Lys (GRKRK) motif and is primarily involved in cell interactions. Front. All authors contributed to writing and editing the review. 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). 220, 312324. Computational smart polymer design based on elastin protein mutability. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. J. Biol. Today Biol. Tropoelastin interacts with microfibril components including fibrillin-1, fibulin-4, and -5, and other associated molecules such as latent transforming growth factor binding protein-4 (Visconti et al., 2003; McLaughlin et al., 2006; Urban et al., 2009; Yamauchi et al., 2010; Noda et al., 2013; Lockhart-Cairns et al., 2020). 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). 9:eaai7466. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. 282, 1248412491. 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: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Tropoelastin - an overview | ScienceDirect Topics Bioeng. 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. (1995). Tropoelastin massively associates during coacervation to form quantized protein spheres. (2006). doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. 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. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. Nature 246, 461466. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Acad. 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. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed Figure 2. (2015). The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. Sci. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Anal. 98, 416. doi: 10.1111/j.1749-6632.1991.tb17013.x, Mecham, R. P., Levy, B. D., Morris, S. L., Madaras, J. G., and Wrenn, D. S. (1985). 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). 37, 698702. *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. Exp. 69, 89102. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. Detailed Description: 19:e1800250. AW is the Scientific Founder of Elastagen Pty. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. 300, 13351359. Acad. Form. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. Crosslinking [ edit] After a period of collaboration with the Elastagen team, US biopharmaceutical giant Allergan acquired Elastagen in 2018 for over $350 million in total deal value. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. (2011). 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). J. Biol. Targeted modulation of tropoelastin structure and assembly. Mater. (2016). Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. KP domains are found closer toward the N-terminus, whereas KA domains are closer to the C-terminus and include alanine tracts (Indik et al., 1987). Although there is no 3D structure for porcine tropoelastin, porcine tropoelastin differs from that of humans (Sandberg et al., 1977), leaving it unclear as to whether these domains align as expected in human tissue. Biosynthesis and nature of elastin structures. 289, 14671477. Nature 437, 9991002. 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). The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. Biochim. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Model. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Chem. 280, 3052630537. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. (2017). Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Cell Biol. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. 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. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. (2008). Transl. Tropoelastins flexibility does not allow it to pack into a crystal lattice and its size renders it too complex to assign atomic interactions using nuclear magnetic resonance (NMR) on a global level (Tamburro et al., 2003, 2006; Bochicchio et al., 2004; Pepe et al., 2008). A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Matrix Biol. Proc. Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. doi: 10.1002/jcp.20546, Kozel, B. Proc. Proc. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Biochemistry 45, 95189530. ELN gene: MedlinePlus Genetics Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Tropoelastins sequence and domain arrangement. Cellular expression of tropoelastin mRNA splice variants. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Tropoelastin - PubMed Coacervation characteristics of recombinant human tropoelastin Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. 432, 57365751. 396, 870873. J. Mol. J. Biol. 87, 18281834. Unlike hydrophobic domains, cross-linking domains in isolation are unable to self-assemble; thus, they have been studied in the context of the cross-linking of elastin-derived biomaterials (Annabi et al., 2017; Yue et al., 2017). Adv. Rep. 8, 116. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Elastin-like polypeptides as models of intrinsically disordered proteins. The lysines of domain 15 and 17 are believed to play key roles in this interaction. Cell Physiol. Biophys. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. The N-terminal head caps an extended coil region that consists of domains 2-18. Biol. Micron 41, 268272. 15, 786801. The hydrophobic domains have been extensively studied and are responsible for facilitating tropoelastins ability to self-assemble (Vrhovski et al., 1997; Toonkool et al., 2001). 266, 308314. Arch. Sci. To get started with texting, you will need: Your phone number The alignment of these three domains indicates that at least two tropoelastin molecules are required to form this tetrafunctional cross-link, thus, giving rise to the head-to-tail model of assembly involving the growth of a linear chain that can assemble laterally to form sheets and eventually form spherules (Baldock et al., 2011). Gene 154, 159166. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Tropoelastins hydrophobic domains are predominantly responsible for the random coil content of the monomer, and are the result of the unique pairing of proline and glycine pairs that are interspersed throughout the majority of hydrophobic domains (Rauscher and Pomes, 2017). Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Implications for microfibril and elastic fiber assembly. Am. 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). Acta 761, 1722. Imaging 11:e007303. Acta 303, 363369. 22, 109121. Elastin - Wikipedia Subtle balance of tropoelastin molecular shape and flexibility 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: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). 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). J. Biochem. FEBS J. J. Med. J. Biol. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. Matrix 12, 156162. Solving tropoelastins global structure (Baldock et al., 2011) allowed for 3D mapping on tropoelastin of the approximate locations of domains 10, 19, and 25, which were the first unequivocally cross-linked domains to be discovered (Brown-Augsburger et al., 1995). 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. Biopolymers [Epub ahead of print]. 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. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). doi: 10.1002/bip.1981.360200611. (1987). 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. A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With 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). Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease.
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