Sci. Furthermore, the SAXS/SANS structure has been mapped to an elastic network model with tunable stiffness to probe the role of tropoelastins flexibility in fiber assembly (Yeo et al., 2016). Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Specific instructions are found in the Directions for Use. Gene 154, 159166. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Biochemistry 8, 28332837. Colloid Interface Sci. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Dermatol. Cell. Thus, computational approaches can be considered as important means to complement wet bench experiments. FEBS J. (1995). The smooth muscle cell. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. 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). doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. II. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Characterization of the complete human elastin gene. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Matrix Biol. Elastin synthesis and fiber assembly. Proc. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 10, 15321541. Chem. (2006). 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). Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Mol. Co-author Professor Anthony Weiss from the Charles Perkins Centre and Faculty of Science explained: "Tropoelastin can repair the heart because it is a precise replica of the body's natural elastic protein,". Tropoelastin is a low complexity protein on both primary and secondary sequence levels. Biol. doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. 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). Acad. 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". 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). (2006). Chemistry 10, 31663176. Biochem. Matrix Biol. J. Biol. J. Med. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. 275, 2844928454. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. (1973). (2005). Molecular modeling of protein materials: case study of elastin. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). Free energy determinants of secondary structure formation: I. alpha-Helices. 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). Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Parameter, Testing, and Method. (2018). J. 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). 282, 1248412491. Elastagen's technology is based on human tropoelastin . Cell Biol. DEERFIELD, IL - Caterpillar Inc. (NYSE: CAT) today announced it will move its global headquarters to the company's existing office in Irving, Texas, from its current location in Deerfield, Illinois. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Am. U.S.A. 110, 28522857. Hydrophobic domains of human tropoelastin interact in a context-dependent manner. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Chem. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. 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.. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. 98, 416. The alignment of the tropoelastin aggregates . Biol. J. Biol. Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). 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). Acad. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Transl. All rights reserved. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. J. Biol. Dyn. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. The lysines of domain 15 and 17 are believed to play key roles in this interaction. doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). (2019a). Genet. Earnings, adjusted for non-recurring costs, came . 2:e1501145. The most crucial of these properties is the ability to undergo many stretch-recoil cycles whilst maintaining the structural and functional integrity of elastic tissues over an organisms lifetime. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Calorim. Possible role in nucleated assembly. 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. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. 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). The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. J. Biol. Biomaterials 139, 163171. Indeed, cryo-EM was recently reported to have a lower molecular size limit of approximately 50 kDa, however, it has not yet been successfully applied to characterize tropoelastin (Murata and Wolf, 2018). Characterization of an unusual tropoelastin with truncated C-terminus in the frog. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). For this injection, the researchers used a new . 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. 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. doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. (2018). 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). Structural changes and facilitated association of tropoelastin. 38, 280291. For many years it was difficult to study tropoelastin at an atomic scale, but the application of computational methods, such as full-atomistic molecular dynamics and elastic network models, in combination with powerful low-resolution structural studies, have expanded the field and delivered an enhanced understanding of the mechanisms that contribute to self-assembly. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. 9:eaai7466. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. Eng. 589(19 Pt A), 24772486. J. Biol. 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. eLife 6:e26526. Chem. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Biomacromolecules 18, 599609. 286, 35943610. 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. PLoS One 7:e46130. 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. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). Matrix Biol. Elastin synthesis during perinatal lung development in the rat. FEBS J. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. Am. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Figure 2. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Dermatol. 249, 997998. Bioeng. 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. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. 43, 131138. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). (2018). Sci. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. Unsubstituted models are also critical to understanding self-assembly. 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). 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. 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.

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