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FEBS Lett. 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. Allergen Acquires Elastagen - pharmasalmanac.com Collapse Section. 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). Proc. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. Elastin-like polypeptides as models of intrinsically disordered proteins. (2007). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). 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). 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. Sci. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Chem. III. Elastin is a critical skin protein consisting of crosslinked tropoelastin. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). 589(19 Pt A), 24772486. (2006). Proc. 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. Natl. J. Biochem. doi: 10.1002/jcp.20546, Kozel, B. 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. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. 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: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Chem. Chem. 264, 88878891. 270, 1777817783. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 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 smooth muscle cell. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). (2012). 98, 416. 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). Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. 249, 997998. Elastin - Wikipedia Unsubstituted models are also critical to understanding self-assembly. 4, 508524. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. Partridge, S. M. (1966). Engineering a highly elastic human protein-based sealant for surgical applications. U.S.A. 110, 28522857. 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. 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. 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). Biochemistry 45, 95189530. (2019b). Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. Healthcare Investment Banking - The Walden Group The ELN gene provides instructions for making a protein called tropoelastin. 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). 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). Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 281, 2375723765. Elastin synthesis during perinatal lung development in the rat. Advanced BioMatrix - Recombinant Tropoelastin, Lyophilized #5052 doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. J. Biol. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. 3, 4 Elastin has a very low rate of turnover, so it . (2014). In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. 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. The liquid structure of elastin. A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Allergan Snaps Up Sydney Biotech for Upfront Payment of US $95M Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). J. Biol. J. February 14, 2018 Michael Patrini. 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. The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Developing elastic tissue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). This model revealed that tropoelastin maintains a canonical or average structure based on the distribution of its possible conformations in spite of its flexible nature (Figure 2), as well as the possible roles that local structures play in biological processes, specifically, elastogenesis (Tarakanova et al., 2019b). Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Molecular modeling of protein materials: case study of elastin. 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. Domain 26 of tropoelastin plays a dominant role in association by coacervation. The N-terminal head caps an extended coil region that consists of domains 218. 410, 317323. 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. Genet. This process is reversible and thermodynamically controlled and does not require protein cleavage. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. 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). Allergan to acquire University of Sydney spinoff Elastagen 126, 563574. 207, 8796. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. 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. J. Struct. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. Proc. Elastin is heterogeneously cross-linked. Natl. Biosynthesis and nature of elastin structures. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Tropoelastins sequence and domain arrangement. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With Allergan to acquire Australian biotech company Elastagen (1977). Pathol. Tropoelastin: a versatile, bioactive assembly module. Res. Allergan's Acquisition of Elastagen - Global Legal Chronicle Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Structure 14, 16671676. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. doi: 10.1016/j.biocel.2008.03.017, Wise, S. G., Yeo, G. C., Hiob, M. A., Rnjak-Kovacina, J., Kaplan, D. L., Ng, M. K., et al. (2011). J. Biol. Adv. Cell Physiol. The first successful experiments to define the 3D envelope of tropoelastin utilized small angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) (Baldock et al., 2011). Nature 437, 9991002. Eng. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Matrix Biol. 120, 419426. 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 (2019). 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. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). 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). 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. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. The conserved C-terminus is an area of the molecule of particular biological importance in that it is required for both incorporation into elastin and for cellular interactions. J. Biol. Molecular docking studies utilizing tropoelastin and the 3D structure of LOX1 (Vallet et al., 2018) may assist in our understanding as to whether the enzyme has a preference for modifying particular tropoelastin residues. (2020). Fell muir lecture: collagen fibril formation in vitro and in vivo. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Biochem. Novel Recombinant Tropoelastin Implants Restore Skin Extracellular Res. 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. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. (2017). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Mol. Pharm. A., and Rucker, R. B. 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. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Elastin is highly hydrophobic, extensively cross-linked, and is assembled into elastic fibers in a dynamic process involving cells, cell surface receptors, and numerous elastic fiber . The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 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,". J. Biol. Acad. Arch. Clinical Relevance of Elastin in the Structure and Function of Skin Chem. 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). Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. (2013). Biophys. Macromol. (2003). 26, 115124. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Acta Histochem. Pharmacol. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Biophys. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Ann. ACS Biomater. (2020). Acad. 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. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . (2017). doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). (1995). doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). ELN gene: MedlinePlus Genetics U.S.A. 109, 28782883. 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). (2009). Natl. 26, 17001709. 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). Tropoelastin is a low complexity protein on both primary and secondary sequence levels. Anal. Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). Front. doi: 10.1002/bip.1981.360200611. Biochemistry 36, 84138421. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. doi: 10.1073/pnas.1014280108. (1988). doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). 289, 489492. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. J. Med. 29, 152159. Sci. Biopolymers 29, 16991706. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. 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). Invest. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Cell Biol. Tropoelastin is a flexible molecule that retains its canonical shape. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Studies on the reduction of elastin. (2015). Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). Chem. Characterization of the complete human elastin gene. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Cell Res. 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). Elastic fibers provide tissues with mechanical resilience, durability, and cell interactivity, which support a diverse range of specialized functionality. Albert, E. N. (1972). 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. All rights reserved. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. KA domains were initially thought to form -helices and poly-proline II helices (PPII) due to the presence of cross-links which require a lysine arrangement that was postulated to be achieved via -helical configuration (Brown-Augsburger et al., 1995). 22, 109121. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. 68, 411419. Matrix Biol. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). 284, 22162230. Proc. DEERFIELD, IL - Caterpillar Inc. (NYSE: CAT) today announced it will move its global headquarters to the company's existing office in Irving, Texas, from its current location in Deerfield, Illinois.