Res. 282, 1248412491. U.S.A. 115, 73387343. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). 43, 131138. 275, 2844928454. Natl. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). J. Biol. (2014). J. Biol. Pharmacol. Med. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. (2017). J. Biol. Elastin is extensively cross-linked and difficult to break apart into monomers even under harsh conditions, thus, initial strategies included feeding animals a copper deficient diet to prevent lysyl oxidase (LOX) cross-linking of tropoelastin; however, this proved inefficient and time consuming (Wise and Weiss, 2009; Tarakanova et al., 2018). (2001). FEBS J. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. Micron 41, 268272. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Tropoelastin is a flexible molecule that retains its canonical shape. Acad. The authors wrote and submitted this manuscript in response to an invitation by the Editor. 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. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Form. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. Tropoelastin - an overview | ScienceDirect Topics All rights reserved. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Chem. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. (2005). For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Parameter, Testing, and Method. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. (2018). doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. Specific instructions are found in the Directions for Use. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. 286, 35943610. 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. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Biol. 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). (2015). For more information, visit Allergans website atwww.Allergan.com. Advanced BioMatrix - Recombinant Tropoelastin, Lyophilized #5052 ACS Biomater. Free energy determinants of secondary structure formation: I. alpha-Helices. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late The hydrophobic domains vary in length, with the majority of the shorter (95 residues) domains occurring near the N-terminus, while the longer (up to 55 residues) domains are found within tropoelastins central and C-terminal regions (Indik et al., 1989). Sci. Matrix Biol. 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). doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Allergan's Acquisition of Elastagen. Chem. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). Allergan Snaps Up Sydney Biotech for Upfront Payment of US $95M Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). Proc. Biochemistry 42, 1334713362. Sci. 34, 8190. Allergan Highlights Key Growth Drivers for Medical Aesthetics Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. Am. doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). J. Biol. Acad. 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). doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Cell Physiol. Clinical Relevance of Elastin in the Structure and Function of Skin Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas Pathol. 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). (2014). Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). J. Biochem. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). Chem. Partridge, S. M. (1966). doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). 258, 118. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Elastin is one of the most abundant proteins in your body. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Sci. 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.. Acad. 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). J. Biol. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. A., Starcher, B. C., and Urry, D. W. (1974). Self-healing and thermoreversible rubber from supramolecular assembly. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. J. Biomol. doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Chem. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. (2017). Biol. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. 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). Natl. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. J. Biol. 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). Anal. Cell Res. Natl. Allergans success is powered by our global colleagues commitment to being Bold for Life. 289, 489492. (2020). This suggests the ERCs primary signal pathways are involved in wound recognition through fragments of elastin, where EDPs are formed as a result of elastic tissue damage. Tropoelastin has 2 alternating domains: (1) hydrophilic, cross-linked, domains rich in Lys and Ala; and (2) hydrophobic domains (responsible for elasticity) rich in Val, Pro, and Gly, which often occur in repeats of VPGVG or VGGVG. Studies on the reduction of elastin. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. Earnings, adjusted for non-recurring costs, came . doi: 10.1016/j.matbio.2007.05.005, He, D., Miao, M., Sitarz, E. E., Muiznieks, L. D., Reichheld, S., Stahl, R. J., et al. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed Biochemistry 37, 1461314622. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). (2017). 3, 4 Elastin has a very low rate of turnover, so it . Proc. Scientists find way to heal scars left behind by heart attacks Coacervation characteristics of recombinant human tropoelastin. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). IRVING, Texas (AP) IRVING, Texas (AP) Fluor Corp. (FLR) on Tuesday reported fourth-quarter net income of $9 million, after reporting a loss in the same period a year earlier. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Int. Mol. Plus 2:100002. doi: 10.1016/j.mbplus.2019.03.001, Parks, W. C., Roby, J. D., Wu, L. C., and Grosso, L. E. (1992). 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. J. Biol. Tropoelastin is frequently described in the literature as an unstructured protein, mainly because models of elasticity invoke an element of disorder within the structure (4, 9, 10).While this concept appears to be the case at the fine, more subtle intramolecular level, chaos alone is unlikely to explain the ordered assembly of tropoelastin which culminates in the formation of organized . J. Med. 13, 739743. Computational smart polymer design based on elastin protein mutability. Elastin synthesis in arterial smooth muscle cell culture. Chem. Tropoelastin. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. 270, 1777817783. A. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Production of recombinant human tropoelastin: Characterization and Acad. (2018). 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). J. Biol. This suggests a high level of conformational sampling during this phase of coacervation, indicating that the flexibility of tropoelastin plays a key role in assembly that may persist, to some extent, into later stages of assembly (Reichheld et al., 2020). The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). We are making enrolling in text alerts easier than ever. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Matrix Biol. Characterization of the complete human elastin gene. 167, 94103. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Natl. A series of mapping studies have been recently conducted to pinpoint the locations of these cross-links (Schrader et al., 2018; Hedtke et al., 2019; Schmelzer et al., 2019) as their placements are crucial to understanding the resultant molecular orientation of tropoelastin within cross-linked elastin. Lab. Elastin, arterial mechanics, and cardiovascular disease doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Chem. Allergan Highlights Key Growth Drivers for Medical Aesthetics - PR Newswire Tropoelastins sequence and domain arrangement. Stages of hierarchical assembly of elastic fibers. 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). 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 importance of tropoelastins flexibility during self-assembly has also been examined in the light of natural allysine modifications, which condense to give cross-links within mature elastin (discussed further in the following section) (Ozsvar et al., 2019). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. J. Biol. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. 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. 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. Biopolymers 107:e23007. Biophys. Synthesis and structural studies of a pentapeptide sequence of elastin. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . Domains 12 to 16 of tropoelastin promote cell attachment and spreading 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: 10.1016/j.ajhg.2009.09.013. Bioeng. Allergan markets a portfolio of leading brands and best-in-class products for the central nervous system, eye care, medical aesthetics and dermatology, gastroenterology, womens health, urology and anti-infectivetherapeutic categories. Protein Eng. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. The smooth muscle cell. The full-atomistic model of tropoelastin was developed based on replica exchange molecular dynamics (REMD) simulations, an accelerated sampling method for molecular dynamics (Tarakanova et al., 2018). On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Biol. Front. Powered by Madgex Job Board Software. J. Exp. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. A., Torres, A. R., Alvarez, V. L., and Janata, J. Sci. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Chem. Allergan's Acquisition of Elastagen - Global Legal Chronicle doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Res. Macromol. Imaging 11:e007303. For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. The hydrophobic domains contain repetitions and variations of Val-Pro-Gly-Val-Gly motifs (Figure 1), resulting in the aforementioned low complexity of sequence (Foster et al., 1973; Gray et al., 1973). (2012). Struct. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Tropoelastin massively associates during coacervation to form quantized protein spheres. Mater. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Matrix Biol. [Epub ahead of print]. J. Therm. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. (2013). Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. 289, 14671477. The ELN gene provides instructions for making a protein called tropoelastin. Unsubstituted models are also critical to understanding self-assembly. We are very interested in the blend of biochemistry and cell biology, as well as the tissue engineering and regenerative medicine opportunities provided by this amazing elastic protein. Sci. Isolation and characterization of crosslinked peptides from elastin. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. 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. 25, 492504. ELN gene: MedlinePlus Genetics For example, models involving single point mutations at negatively charged residues demonstrated both regional and global destabilization of tropoelastins structure, which were validated by SAXS structures (Yeo et al., 2012; Tarakanova et al., 2018). Molecular model of human tropoelastin and implications of associated mutations. doi: 10.1002/bip.1981.360200611. Sci. Fluor: Q4 Earnings Snapshot | AP News 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). Model. B., Broekelmann, T. J., et al. Chem. 27, 441450. Invest. The tropoelastin that Elastagen manufactures is an identical copy of what naturally occurs in human tissue, meaning the clinical application opportunities for this has tremendous potential . 37, 698702. 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). J. Mol. doi: 10.1016/s0934-8832(11)80057-0. Biomacromolecules 18, 599609. Acta Biomater. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations.