The lysines of domain 15 and 17 are believed to play key roles in this interaction. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. J. Med. 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. Invest. Biochemistry of tropoelastin. Biophys. Mol. 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. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). 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. Front. Nature 451, 977980. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Elastin is heterogeneously cross-linked. 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). doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). Biomaterials 139, 163171. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Conformational transitions of the cross-linking domains of elastin during self-assembly. Lab. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Acta Histochem. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). J. Biol. J. 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). doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. 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). Tropoelastin: a versatile, bioactive assembly module. doi: 10.7554/eLife.26526. This process is reversible and thermodynamically controlled and does not require protein cleavage. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Biopolymers 29, 16991706. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Detailed Description: On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. (2005). Eur. 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). Biopolymers [Epub ahead of print]. 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. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. 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 . Due to the lack of a full-atomistic structure, a number of elastin derivatives, including isolated tropoelastin domains (Toonkool et al., 2001; Mackay et al., 2005; Dyksterhuis et al., 2007; Dyksterhuis and Weiss, 2010) and synthetic elastin-derived peptides (EDPs) (Luan et al., 1990; Tamburro et al., 1992; Kentsis and Sosnick, 1998; Kumashiro et al., 2006; Reichheld et al., 2014, 2017; Muiznieks et al., 2015; MacEwan et al., 2017; Tarakanova et al., 2017) have been studied to understand tropoelastins domain level properties. Ltd., which was sold to Allergan, now a division of AbbVie. 280, 3052630537. Biochemistry 42, 1334713362. 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). Matrix Biol. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Elastic fibers provide tissues with mechanical resilience, durability, and cell interactivity, which support a diverse range of specialized functionality. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Nat. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. (2019b). [Epub ahead of print]. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. 34, 8190. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). Biomaterials 127, 4960. Characterization of the complete human elastin gene. 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 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. Res. 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). doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). A new amino acid from hydrolysates of elastin. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). EBP plays two roles in the assembly of elastin. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). 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. Sci. Sci. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. (2012). Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. Transl. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Cytochem. Synthesis and structural studies of a pentapeptide sequence of elastin. FEBS J. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). 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. Structure 14, 16671676. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. 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). Biol. (2005). Allergan's Acquisition of Elastagen. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. 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). 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.. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Rep. 8, 116. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Proc. 289, 489492. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. 167, 94103. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Fabricating organized elastin in vascular grafts. Coacervation characteristics of recombinant human tropoelastin. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. 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). Cellular expression of tropoelastin mRNA splice variants. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. 280, 4093940947. A comprehensive map of human elastin cross-linking during elastogenesis. 84, 6880. 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).
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