Res. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Chem. 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: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. 1862, 324334. Detailed Description: Acad. 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). In addition to its involvement in molecular elasticity, the flexibility of tropoelastin also a key requirement for self-assembly into elastin, with mutations that perturb this having detrimental effects on tissue (Yeo et al., 2016, 2017). It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. 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. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Dermatol. Ltd., which was sold to Allergan, now a division of AbbVie. Pharmacol. (2014). 19:e1800250. 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. Biochimie 86, 173178. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Biochemistry 8, 28372845. Banded fibers in tropoelastin coacervates at physiological temperatures. (2005). Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Unsubstituted models are also critical to understanding self-assembly. Tropoelastin #5052. J. Ultrastruct. 126, 283290. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. Self-healing and thermoreversible rubber from supramolecular assembly. 275, 2844928454. Acad. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. Developing elastic tissue. 276, 4457544580. Chemistry 10, 31663176. For more information, visit Elastagens website atwww.elastagen.com. *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. Figure 2. 284, 22162230. 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). EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). 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: 10.1073/pnas.1014280108. Lyophilized Powder. Pathol. Acta Gen. Subj. 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. Figure 1. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Lab. Fibrillin-1 interactions with heparin. Fibulin-4 and -5, but not fibulin-2, are associated with tropoelastin deposition in elastin-producing cell culture. doi: 10.1016/j.ajhg.2009.09.013. 3, 4 Elastin has a very low rate of turnover, so it . Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. J. Mol. Natl. 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. An electron microscopic study. Molecular model of human tropoelastin and implications of associated mutations. Front. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. (2015). (2006). 289, 489492. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. doi: 10.1016/j.bbrc.2010.05.013, Elvin, C. M., Carr, A. G., Huson, M. G., Maxwell, J. M., Pearson, R. D., Vuocolo, T., et al. Computational approaches have gained popularity in recent decades as their methodologies have been refined to provide accurate atomistic scale insights into molecular structure and movement (Tarakanova et al., 2018). Tropoelastins primary sequence is low in complexity and contains repetitive motifs. Chem. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. J. Biol. Matrix Biol. 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. 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). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. Biopolymers 20, 12471260. Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). Elastogenesis in human aorta: an electron microscopic study. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). 300, 13351359. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Bull. J. Biol. Acad. (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). Pharm. 281, 2375723765. Biophys. Structure 14, 16671676. (2014). 58, 270277. 280, 4093940947. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). 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. (2009). In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. Nature 437, 9991002. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). 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). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Powered by Madgex Job Board Software. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. FEBS J. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Tropoelastin massively associates during coacervation to form quantized protein spheres. Chem. Conformational transitions of the cross-linking domains of elastin during self-assembly. (1995). 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). Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. 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). Natl. U.S.A. 109, 28782883. 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. Fabricating organized elastin in vascular grafts. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. 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. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). For example, their inclusion in peptides derived from hydrophobic domains confers decreased times taken for self-assembly, most likely due to their favorable interaction with aqueous solvent (Miao et al., 2003). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. 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. (2003). doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Gene 154, 159166. 258, 118. J. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. Sci. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). J. Biochem. Exp. 260, 32553258. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. 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. 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). Commun. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). The coacervate is made insoluble by irreversible crosslinking. Acta Biomater. It has recently been suggested that fibrillins are capable of stabilizing tropoelastin, possibly for the purpose of selecting conformations that are favorable for elastin assembly (Lockhart-Cairns et al., 2020). doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. Natl. Cooperativity between the hydrophobic and cross-linking domains of elastin. Cell Biol. Biochemistry 45, 95189530. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. Chem. 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. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. doi: 10.1002/bip.1981.360200611. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. 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). (2007). Chem. Sci. Cell Biol. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. 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. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Poly (Val-Gly-Gly-Leu-Gly). Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. . Biotechnol., 25 February 2021, View all 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. (2017). 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). doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. 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 . Macromol. Delineation of unusual features in the 5-flanking region. (2019). Matrix Biol. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. 589(19 Pt A), 24772486. Am. This process is reversible and thermodynamically controlled and does not require protein cleavage. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Mol. Elastagen Pty Ltd, 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 plc, a leading global biopharmaceutical company, has agreed to acquire Elastagen. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 98, 416. 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. J. Biol. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. 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. Tropoelastin: a novel marker for plaque progression and instability. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Tropoelastins domains each arise from single exons of the ELN gene. Biophys. J. Biol. doi: 10.1038/nature06669, Cox, B. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . The amino acid sequence of domain 36 is unique; furthermore, its sequence confers a positively charged C-terminus comprising lysines between positively charged arginines, forming a RKRK sequence (Vrhovski et al., 1997). I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Synthesis and properties of crosslinked recombinant pro-resilin. Form. Coacervation involves the agglomeration of protein molecules, which is an . Direct observation of structure and dynamics during phase separation of an elastomeric protein. 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. The authors wrote and submitted this manuscript in response to an invitation by the Editor. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. Biotechnol. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. 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).
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