For more information, visit Allergans website atwww.Allergan.com. doi: 10.1073/pnas.1014280108. Circ. 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". Calorim. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Baul, U., Bley, M., and Dzubiella, J. Biopolymers 107:e23007. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Proc. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. (1995). Characterization of an unusual tropoelastin with truncated C-terminus in the frog. J. Biomol. Front. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. 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]. Cellular expression of tropoelastin mRNA splice variants. Matrix Biol. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas Biosynthesis and nature of elastin structures. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. 278, 4855348562. Targeted modulation of tropoelastin structure and assembly. 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). Mater. Chem. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. 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. Cell Physiol. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. (2017). 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). Synthesis and properties of crosslinked recombinant pro-resilin. Int. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. Acad. (2001). Proc. The N-terminal head caps an extended coil region that consists of domains 218. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Tropoelastin - PubMed 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). Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. Thus, elastin is responsible, in great part, for the properties of elastic fibers. 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). Natl. Fluor: Q4 Earnings Snapshot | AP News Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. Elastagen's technology is based on human tropoelastin . Matrix Biol. Molecular modeling of protein materials: case study of elastin. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. 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. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. Biochemistry 42, 1334713362. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. FEBS J. (2016). Chem. Tropoelastin is frequently described in the literature as an unstructured protein, mainly because models of elasticity invoke an element of disorder within the structure (4, 9, 10).While this concept appears to be the case at the fine, more subtle intramolecular level, chaos alone is unlikely to explain the ordered assembly of tropoelastin which culminates in the formation of organized . Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. 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. J. Direct observation of structure and dynamics during phase separation of an elastomeric protein. (2019b). For more information, visit Elastagens website atwww.elastagen.com. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. In contrast, higher temperatures allow the breaking of the hydrogen bonds of the ordered water, dissipating the clathrate shells and permitting the association of the hydrophobic domains (Yeo et al., 2011). Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. Figure 1. Am. All authors contributed to writing and editing the review. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. (2005). Soluble matrix protein is a potent modulator of mesenchymal stem cell Pathol. Genet. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Coacervation characteristics of recombinant human tropoelastin Coacervation characteristics of recombinant human tropoelastin. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. Chem. The lysines of domain 15 and 17 are believed to play key roles in this interaction. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Chem. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. (1987). The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. 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). 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. 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). (2013). Shape of tropoelastin, the highly extensible protein that - PNAS 82, 335340. (2008). Biomaterials 139, 163171. J. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Allergans success is powered by our global colleagues commitment to being Bold for Life. 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. 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). Chem. Production of recombinant human tropoelastin: Characterization and This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). FEBS J. 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). Biopolymers [Epub ahead of print]. J. Struct. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). 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). Coarse-grained model of tropoelastin self-assembly into nascent fibrils. 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. Allergen Acquires Elastagen - pharmasalmanac.com Trends Biotechnol. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 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. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). 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). Proc. 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). 250, 9298. Hydrophobic domains of human tropoelastin interact in a context-dependent manner. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. (2019). The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. 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). 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). The compositions include a coalescence-controlling agent in the form of a polysaccharide or polysaccharide derivative, in an amount effective for providing the substance with the properties of flow, enabling injection. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance. 28, 379382. Dyn. A., Gray, W. R., and Franzblau, C. (1973). 26, 115124. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Frontiers | Tropoelastin and Elastin Assembly Differential expression of two tropoelastin genes in zebrafish. (2015). A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). eLife 6:e26526. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. doi: 10.1021/bi981641y, Kozel, B. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). 264, 88878891. 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. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Am. (2018). 289, 14671477. II. Clinical Relevance of Elastin in the Structure and Function of Skin Four days after a heart attack, purified tropoelastin was injected into the heart. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 37, 698702. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Biosci. Biopolymers 29, 16991706. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Tropoelastin: a versatile, bioactive assembly module. U.S.A. 110, 28522857. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. 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). 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. 252, 351365. *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. 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). 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). 270, 1777817783. Lysinonorleucine. 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). Self-healing and thermoreversible rubber from supramolecular assembly. Form. 33, 54685481. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. Nature 246, 461466. 4, 508524. Sci. Elastin is heterogeneously cross-linked. Allergan to acquire Australian biotech company Elastagen Dermatol. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. 260, 32553258. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. Chem. (1989). 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). 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. Allergan's Acquisition of Elastagen. Patient Homepage | Accredo J. Med. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Proc. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Biophys. (2015). [Epub ahead of print]. 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. Simul. Chem. 284, 22162230. 589(19 Pt A), 24772486. Rush to Beauty Anticipates New Line of Dermal Fillers from Allergan J. Mol. Cooperativity between the hydrophobic and cross-linking domains of elastin. Specific instructions are found in the Directions for Use. Tropoelastin, the raw material used to create 'MeTro' elastic surgical glue developed with the University of Sydney, has been found to encourage stem cell growth - with the potential to ultimately help the body repair itself. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. 98, 416. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. Domains 12 to 16 of tropoelastin promote cell attachment and spreading
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