Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Its estimated half-life of 70 years (Shapiro et al., 1991) is due to its extensive cross-linking and high hydrophobicity, which render it resistant to degradation (Vrhovski and Weiss, 1998; Schrader et al., 2018; Hedtke et al., 2019). 289, 14671477. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. Biochem. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Communication: coacervation of tropoelastin results in fiber formation. Matrix Biol. A comprehensive map of human elastin cross-linking during elastogenesis. (2005). A. All rights reserved. Pharm. The coacervate is made insoluble by irreversible crosslinking. Crosslinking [ edit] Natl. Chem. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. 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 business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. 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). The ELN gene provides instructions for making a protein called tropoelastin. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. 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). This reflects the experimentally observed heterogeneity of cross-links in mature elastin, again giving weight to the hypothesis that the flexibility of tropoelastin is imperative for assembly (Schrader et al., 2018; Tarakanova et al., 2019a). Domain 26 of tropoelastin plays a dominant role in association by coacervation. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). Trends Biotechnol. (2001). The cross-linking domains are enriched for either Lys-Pro (KP) or Lys-Ala (KA) motifs and form cross-links that link growing tropoelastin chains during elastogenesis; note that exon 6 encodes a KA domain. A., Gray, W. R., and Franzblau, C. (1973). The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 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. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Mol. Matrix Biol. Biochim. Lyophilized Powder. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. 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. J. Biol. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). doi: 10.1016/j.ajhg.2009.09.013. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. J. Biochem. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. Elastin-like polypeptides as models of intrinsically disordered proteins. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . (2003). Proc. Circ. doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Allergan is an industry leader in Open Science,a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. Rep. 8, 116. J. Biomol. Elastin biomaterials in dermal repair. Fluor: Q4 Earnings Snapshot. Water structure and elastin-like peptide aggregation. 167, 94103. (1983). Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. 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). 79, 277284. 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). doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). 396, 870873. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Macromol. 126, 563574. Cooperativity between the hydrophobic and cross-linking domains of elastin. By probing mutations in computational studies that resolve the atomistic structure of the molecule, the deduction of mechanisms associated with changes to functional roles of specific domains has become feasible, and a connection between local structures and biological performance can be established (Figure 2; Tarakanova et al., 2018). With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Cytochem. Molecular dynamics modeling of aggregating tropoelastin-derived peptide chains points to the maintenance of a hydrated, disordered, liquid-like state due to the formation of short-lived inter-chain bonds (Rauscher and Pomes, 2017; Reichheld et al., 2020), mostly likely due to the inducement of random coils by PG repeats (vide supra). The conversion of a single lysine to an allysine results in structural stabilization, which may serve as a checkpoint during self-assembly to ensure that molecules incapable of forming multiple cross-links are not incorporated into the growing chain. Chem. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). (1965). doi: 10.1038/nature04085. 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). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). 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. Biomacromolecules 18, 599609. 19:e1800250. B., Broekelmann, T. J., et al. Matrix 12, 156162. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. J. Biol. Synthesis and properties of crosslinked recombinant pro-resilin. Elastagen's technology is based on human tropoelastin . Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). For more information, visit Elastagens website atwww.elastagen.com. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. (2007). N. Y. Acad. III. Acad. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Proc. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. 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. (2020). The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Biophys. Imaging 11:e007303. A model two-component system for studying the architecture of elastin assembly in vitro. 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). Biochem. Biochim. 270, 1777817783. Biopolymers [Epub ahead of print]. Lab. Nat. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. Matrix Biol. Elastogenesis in human aorta: an electron microscopic study. Model. Genet. doi: 10.1073/pnas.1014280108. Figure 2. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance. [Epub ahead of print]. J. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). (1988). 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. 220, 312324. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. Interestingly, the location and orientation of different domains that contacted each other during self-assembly was noted to be heterogeneous, resulting in head-to-head, tail-to-tail, head-to-tail, and lateral interactions (Tarakanova et al., 2019a). The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). J. Mol. J. Hum. 260, 32553258. 85, 593605. 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). Self-healing and thermoreversible rubber from supramolecular assembly. Chem. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. Chem. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. Characterization of the complete human elastin gene. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. 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. Biomaterials 139, 163171. 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). (2015). 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 . Front. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). Integrins are a major class of cell surface receptor family, of which tropoelastin has been found to interact with two types: v3 (Rodgers and Weiss, 2004) and v5. Biochemistry 36, 84138421. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Lysinonorleucine. However, there are aspects of this model that warrant further investigation. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 266, 308314. Approximately 90% of tropoelastins lysines undergo modification and/or participate in cross-links, indicating that mature elastin is extensively cross-linked (Kozel et al., 2003; Schmelzer et al., 2019). The lysines of domain 15 and 17 are believed to play key roles in this interaction. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). Form. U.S.A. 115, 73387343. 26, 125135. 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. (1995). We are making enrolling in text alerts easier than ever. Res. (2018). doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. 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. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. 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). Biol. Mol. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Ltd., which was sold to Allergan, now a division of AbbVie. 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). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Molecular modeling of protein materials: case study of elastin. The narrow specificity to v3 and 53 may also be beneficial compared with other ECM adhesion molecules such as fibronectin (which can adhere to up to 20 types of integrin) which may compete with and modulate binding to tropoelastin, and deliver opposing effects on cell proliferation. 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). (1989). Modeling utilizing tropoelastin derivatives has demonstrated that structural compaction into both coils and globules occurs above the transition temperature of self-assembly, which may assist in explaining the anisotropic nature of mature elastin (Baul et al., 2020). 98, 416. Biochemistry 52, 77317741. 289, 1005710068. (1977). Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). 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). Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. Allergan's Acquisition of Elastagen. 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). *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. J. Biol. Biol. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. Targeted modulation of tropoelastin structure and assembly. Med. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 33, 54685481. Further to this, the current model of elastin assembly does not account for how long strings or sheets of tropoelastin are capable of forming spherules on a macroscopic scale (Tu et al., 2010). 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. 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. Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). Eur. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. 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". U.S.A. 112, E4408E4415. 3, 4 Elastin has a very low rate of turnover, so it . Coacervation characteristics of recombinant human tropoelastin. 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). The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Res. Implications for tissue specificity and durability of elastic tissue. Nature 451, 977980. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. 10, 15321541. 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. 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. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Natl. Structure 14, 16671676. 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).
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