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. 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. J. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Scientists find way to heal scars left behind by heart attacks 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. Novel Recombinant Tropoelastin Implants Restore Skin Extracellular doi: 10.1002/chem.200305661. Cell Biol. Parameter, Testing, and Method. U.S.A. 109, 28782883. 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. Tropoelastin - an overview | ScienceDirect Topics doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). Production of recombinant human tropoelastin: Characterization and (2006). Elastin is heterogeneously cross-linked. Tropoelastin (TE) is the main (>90%) component of elastin, wherein crosslinked assembled coacervates of TE are exposed to lysyl oxidases and interact with microfibrils to expand elastin fibers. 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. 69, 89102. 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. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Tropoelastin has a defined shape in solution but paradoxically also displays a large percentage of flexible, disordered regions needed for molecular elasticity (4, 5).The tertiary structure of human tropoelastin represents an ensemble of elastic conformers (3, 6), yet occasional conserved sequence elements hint at requirements for functional demands in one or more key parts of this molecule (7 . doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. 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. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Tropoelastin Improves Post-Infarct Cardiac Function 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. Structural changes and facilitated association of tropoelastin. 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. 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. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Chem. Proc. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Ann. 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). Due to the lack of a full-atomistic structure, a number of elastin derivatives, including isolated tropoelastin domains (Toonkool et al., 2001; Mackay et al., 2005; Dyksterhuis et al., 2007; Dyksterhuis and Weiss, 2010) and synthetic elastin-derived peptides (EDPs) (Luan et al., 1990; Tamburro et al., 1992; Kentsis and Sosnick, 1998; Kumashiro et al., 2006; Reichheld et al., 2014, 2017; Muiznieks et al., 2015; MacEwan et al., 2017; Tarakanova et al., 2017) have been studied to understand tropoelastins domain level properties. doi: 10.1002/bip.1981.360200611. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. Human ELN gives rise to a broad variety of splice isoforms, with alternative splicing being observed with exons 22, 23, 24, 26A, 32, and 33 (Fazio et al., 1988; Parks et al., 1992) that result in 13 known human isoforms of the mature tropoelastin protein (Reichheld et al., 2019). Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. 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. (2003). 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). Tropoelastin is typically used as a thin coating on tissue culture surfaces. Mater. 26, 125135. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). (1995). Biochemistry 42, 1334713362. Combinations of these two amino acids result in domains that undergo rapid conformational sampling (Rauscher and Pomes, 2017), which, if perturbed toward a conformation that gravitate toward stability, will assemble into highly ordered amyloid-like fibrils that are not elastomeric (Rauscher et al., 2006; Roberts et al., 2015). Rev. Mater. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. 286, 35943610. doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Nature 246, 461466. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Biochem. J. Med. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. 284, 22162230. Mater. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Cell Res. Pharm. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Acta Gen. Subj. U.S.A. 112, E4408E4415. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . 589(19 Pt A), 24772486. Acad. This process is reversible and thermodynamically controlled and does not require protein cleavage. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). This temperature is also known as the transition temperature. 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. 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). Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. 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: 10.1038/nature06669, Cox, B. Biochemistry 45, 95189530. doi: 10.1038/nature04085. 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). We are making enrolling in text alerts easier than ever. Sci. 120, 419426. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). J. Ultrastruct. Chem. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). Proc. Res. 260, 32553258. Simul. Variations in the relative abundance of alternatively spliced ELN mRNA transcripts have been observed between tissues, and this diversity is thought to be necessary for the fine tuning of the mechanical characteristics of tissues to suit their unique functional requirements (Reichheld et al., 2019). 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. Cell Physiol. 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. [Epub ahead of print]. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. 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). I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed Sci. Biol. 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. A. 26, 115124. 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). Collapse Section. 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).
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