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Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Poly (Val-Gly-Gly-Leu-Gly). AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Biochim. 286, 35943610. 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). Unsubstituted models are also critical to understanding self-assembly. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. (2005). Tropoelastin massively associates during coacervation to form quantized protein spheres. 9:643110. doi: 10.3389/fbioe.2021.643110. 85, 593605. Mol. A., Starcher, B. C., and Urry, D. W. (1974). Acad. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Mol. For more information, visit Elastagens website atwww.elastagen.com. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). This phenomenon is supported by in vitro peptide studies, which note that increasing the space between PG motifs or removing prolines results in more ordered structures (Rauscher et al., 2006). 7:32. doi: 10.3389/fphar.2016.00032, Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M. P., Jowitt, T. A., Marchand, M. F., et al. Additionally, coarse-graining the full-atomistic model has allowed for the examination of mesoscale tropoelastin assembly and, in particular, deciphered the orientation of tropoelastin molecules that occurs during early stage assembly (inset image) (Tarakanova et al., 2019a). Trends Biotechnol. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Dermatol. J. Hum. (2003). 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. Am. J. Biol. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). 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). 432, 57365751. J. Eng. Bioeng. Collapse Section. Molecular modeling of protein materials: case study of elastin. 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. 275, 2844928454. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. J. Ultrastruct. (2018). (1989). Bonnans, C., Chou, J., and Werb, Z. 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. 126, 283290. Stages of hierarchical assembly of elastic fibers. 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. 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 scars, stretch marks, aesthetic skin repair and wound repair. doi: 10.1002/bip.1981.360200611. doi: 10.1002/jcp.20546, Kozel, B. (2017). Elastin synthesis during perinatal lung development in the rat. Domain 36 of tropoelastin in elastic fiber formation. U.S.A. 115, 73387343. 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 These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Figure 3. J. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. 33, 54685481. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). J. Biomol. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Invest. Acad. 26, 125135. 10, 15321541. 37, 698702. Int. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. 79, 277284. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Matrix Biol. Sci. 25, 10231029. Chem. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Sci. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. 266, 308314. 207, 8796. 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 (). Lyophilized Powder. This acquisition and the development of a next generation of injectables based on this technology will ensure Allergan offers innovative filler products for years to come., Robert Daniels, Elastagen CEO, noted: Partnering with Allergan, a leader in medical aesthetics, is incredibly exciting. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. 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). Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). 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]. Natl. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. 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. 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. eLife 6:e26526. Biochemistry 45, 99899996. Baul, U., Bley, M., and Dzubiella, J. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. 252, 351365. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. 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). Direct observation of structure and dynamics during phase separation of an elastomeric protein. Chem. (2015). 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. Gene 154, 159166. FEBS J. 26, 524540. doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. 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. Albert, E. N. (1972). Thus, elastin is responsible, in great part, for the properties of elastic fibers. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). Eur. U.S.A. 110, 28522857. 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). Tropoelastin. (2013). EBP plays two roles in the assembly of elastin. Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Struct. Cellular expression of tropoelastin mRNA splice variants. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 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. Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Biochemistry 45, 95189530. 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. 220, 312324. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Natl. 293, 1510715119. (2014). In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). 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. Natl. Lysinonorleucine. 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). Eur. Tropoelastin: a versatile, bioactive assembly module. Chem. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). 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). 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. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Hogan Lovells represented Elastagen Pty Ltd. on the deal. A., Torres, A. R., Alvarez, V. L., and Janata, J. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. 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). (2006). Most organisms contain one copy of ELN, other than teleosts and amphibians which notably possess two distinct types of ELN genes (He et al., 2007; Miao et al., 2007, 2009). 26, 17001709. 4, 508524. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. Sci. Partridge, S. M. (1966). Biopolymers 107:e23007. Calorim. 264, 88878891. Acad. (2019). More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). 300, 13351359. (1965). (2019a). Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). FEBS J. 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. On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. It has been postulated that the interaction between tropoelastin and cell surface proteoglycans is part of the assembly process of elastin before it is deposited on microfibrils. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. 41, 494497. 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). Genet. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). (2009). Front. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). Biochem. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. Chem. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). Biosynthesis and nature of elastin structures. 25, 492504. 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. Delineation of unusual features in the 5-flanking region. Matrix Biol. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Acta Biomater. J. Mol. Elastagen's technology is based on human tropoelastin . Front. Identification of an elastin cross-linking domain that joins three peptide chains. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Biol. Biol. Chem. Molecular model of human tropoelastin and implications of associated mutations. Chem. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. (1981). J. Biochem. Exp. Characterization of the complete human elastin gene. 22, 109121. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. 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). 15, 786801. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Detailed Description: PLoS One 7:e46130. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. 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). Developing elastic tissue. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Elastin: molecular description and function. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. 34, 8190. Implications for microfibril and elastic fiber assembly. Furthermore, as integrins are involved in the remodeling of the ECM (Bonnans et al., 2014), this is consistent with a model where the tropoelastin-integrin interaction forms part of the wound repair process. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. 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). (1973). 120, 419426. 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). Biomacromolecules 20, 11781189. Matrix Biol. Trends Biotechnol. A., Gray, W. R., and Franzblau, C. (1973). Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Fell muir lecture: collagen fibril formation in vitro and in vivo. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Fluor: Q4 Earnings Snapshot. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Tropoelastin cannot readily be prepared in quantity from natural sources and this has limited research in several important areas including structure/function relationships and fiber assembly. Lab. 276, 4457544580. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Today Biol. B., Broekelmann, T. J., et al. Nat. Package Size. J. Clin. 3, 28322844. 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). Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Chem. Ltd., which was sold to Allergan, now a division of AbbVie. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. Sci. Possible role in nucleated assembly. Simul. Arch. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Matrix Biol. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). 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). Water structure and elastin-like peptide aggregation. 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.. (1987). Dyn. Comparative genomics of elastin: sequence analysis of a highly repetitive protein.