27, 441450. 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). Cellular expression of tropoelastin mRNA splice variants. 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). doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). 69, 89102. 25, 10231029. Free energy determinants of secondary structure formation: I. alpha-Helices. Elastin biomaterials in dermal repair. 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). 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). Nature 246, 461466. A., Starcher, B. C., and Urry, D. W. (1974). Proc. Chem. (1965). Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). 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 . doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. 33, 54685481. Biopolymers 103, 563573. The N-terminal head caps an extended coil region that consists of domains 218. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). 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). Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. Tropoelastin: a versatile, bioactive assembly module. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). (2013). 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. 79, 277284. Allergans success is powered by our global colleagues commitment to being Bold for Life. (2020). However, there are aspects of this model that warrant further investigation. 207, 8796. Eur. 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. 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. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Coacervation involves the agglomeration of protein molecules, which is an . Lysinonorleucine. 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. This canonical computational structure was determined to be highly similar to the envelope found via SAXS/SANS, where both consist of an extended molecular body accompanied by a protruding foot (Baldock et al., 2011). Natl. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Ltd., which was sold to Allergan, now a division of AbbVie. J. Ultrastruct. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. J. Exp. doi: 10.1002/bip.1981.360200611. Trends towards maximal association are apparent when each of these parameters is varied. 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). Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. No use, distribution or reproduction is permitted which does not comply with these terms. Acta 761, 1722. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. (2003). 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). 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. Targeted modulation of tropoelastin structure and assembly. 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. Biosci. 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 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). Self-healing and thermoreversible rubber from supramolecular assembly. 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). (2019b). The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. doi: 10.7554/eLife.26526. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). 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). (2006). 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). (2020). Elastin is a critical skin protein consisting of crosslinked tropoelastin. The alignment of the tropoelastin aggregates . 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. Acta Biomater. Tropoelastin massively associates during coacervation to form quantized protein spheres. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). 22, 109121. For more information, visit Elastagens website atwww.elastagen.com. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. J. Biochem. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Molecular model of human tropoelastin and implications of associated mutations. Biophys. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Eng. 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. 289, 489492. Acad. (2005). Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. 15, 786801. 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). Bioeng. 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). All rights reserved. Cell Biol. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. (2018). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). 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). With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. Sci. 26, 115124. J. Mol. 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. Synthesis and properties of crosslinked recombinant pro-resilin. Figure 3. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). 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). Allergan's Acquisition of Elastagen - Global Legal Chronicle Cross-linking domains can be subdivided into KP or KA domains, which denote the amino acids (proline or alanine, respectively) that are adjacent to the lysines (Figure 1). Biochemistry 37, 1461314622. Pathol. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. 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). 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). Protein Eng. J. Biol. (1983). Int. Chem. 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). Eur. Res. Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Transl. Mater. Cross-linking requires the modification of at least one of the lysine participants by a member of the copper-containing LOX or lysine oxidase-like (LOXL) enzyme families. Front. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. 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). The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. Nat. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). 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). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. Biomacromolecules 21, 35233538. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Model. Proc. Intracellularly, EBP is associated with tropoelastin after the release of the signal peptide and acts as a chaperone to prevent self-aggregation and proteolysis as it transported to the cell membrane, after which EBP is then recycled and serves as a reusable shuttle protein (Hinek et al., 1995). 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). (2014). 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. 286, 35943610. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. (2007). Am. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. 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). doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). (2014). 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). Chem. Differential expression of two tropoelastin genes in zebrafish. Thus, elastin is responsible, in great part, for the properties of elastic fibers. doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). [Epub ahead of print]. FEBS J. Biol. 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 26, 524540. CICADA TURNS 20: How synthetic skin biotech Elastagen changed lives Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. 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. 293, 1510715119. Our Juvederm collection of fillers has sales of over $1 billion globally and is one of the fastest growing parts of our Aesthetics business, said Bill Meury, Chief Commercial Officer at Allergan. 410, 317323. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Chem. (1995). Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. 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). Acad. U.S.A. 115, 73387343. 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). doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. 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). 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). Meanwhile, modifications to the full-atomistic model have revealed the mechanisms that contribute to aberrant fiber structure (Tarakanova et al., 2018) that have been hypothesized to predispose patients to diseases such as acquired cutis laxa (Hu et al., 2006). doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Implications for microfibril and elastic fiber assembly. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Circ. doi: 10.1016/j.ajhg.2009.09.013. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Tropoelastin: a novel marker for plaque progression and instability. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Allergen Acquires Elastagen - pharmasalmanac.com "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Micron 41, 268272. 284, 22162230. 3, 28322844. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Fluor: Q4 Earnings Snapshot | AP News doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Figure 1. Sci. (2018). Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. Mater. Non-polar residues are a major contributor to protein folding, as their unfavorable interactions with water drive them to bury into the protein core, however, as tropoelastin is comprised of numerous hydrophobic domains, it has been demonstrated that many of these domains will be at least partially solvent exposed (Dyksterhuis et al., 2007). Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . Isolation and characterization of crosslinked peptides from elastin. Acad. Biochimie 86, 173178. doi: 10.1016/j.biomaterials.2017.04.050, Keywords: elastin, elastic fibers, tropoelastin, computational modeling, assembly, Citation: Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A and Weiss AS (2021) Tropoelastin and Elastin Assembly. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Biol. The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). (1988). Tropoelastin is a low complexity protein on both primary and secondary sequence levels. 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). February 14, 2018 Michael Patrini. 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]. Acta 303, 363369. Allergan Plc, a $15.9b provider of medical aesthetics, biosimilars, and over-the-counter pharmaceutical products will acquire Elastagen Pty Ltd., a provider of advanced tissue repair platform based on tropoelastin (gives tissue its elasticity) for $95m.The acquisition adds proprietary injectable products to Allergan's existing portfolio. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. N. Y. Acad. (2019). . 29, 152159. Figure 2. Cell Biol. Patient Homepage | Accredo FASEB J. (2007). 280, 4093940947. 126, 563574. Genet. Possible role in nucleated assembly. 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. Colloid Interface Sci. Studies on the reduction of elastin. J. Biol. 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). The majority of tropoelastin synthesis occurs during perinatal development (Myers et al., 1983; Noguchi et al., 1990), however, synthesis may be triggered in response to tissue damage (Parks et al., 1992) or during diseases such as atherosclerosis (Phinikaridou et al., 2018).
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