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. Mol. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Sci. 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. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. 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. Patient Homepage | Accredo Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. Tropoelastin (TE) is the main (>90%) component of elastin, wherein crosslinked assembled coacervates of TE are exposed to lysyl oxidases and interact with microfibrils to expand elastin fibers. Water structure and elastin-like peptide aggregation. A new amino acid from hydrolysates of elastin. Tropoelastin massively associates during coacervation to form quantized protein spheres. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Cell Biol. 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. Biol. 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. 264, 88878891. Proc. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Elastin is highly hydrophobic, extensively cross-linked, and is assembled into elastic fibers in a dynamic process involving cells, cell surface receptors, and numerous elastic fiber . Med. Elastin: Structure, Function, Skin Care & Supplements - Cleveland Clinic 286, 35943610. 284, 22162230. Acta Gen. Subj. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). (2007). The hydrophobic domain 26 of human tropoelastin is unstructured in solution. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). Colloid Interface Sci. A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With Biol. (2006). Elastin is a critical skin protein consisting of crosslinked tropoelastin. 3, 4 Elastin has a very low rate of turnover, so it . 250, 9298. Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Biochemistry 52, 77317741. 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). Combinations of these two amino acids result in domains that undergo rapid conformational sampling (Rauscher and Pomes, 2017), which, if perturbed toward a conformation that gravitate toward stability, will assemble into highly ordered amyloid-like fibrils that are not elastomeric (Rauscher et al., 2006; Roberts et al., 2015). Biomacromolecules 21, 35233538. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Sci. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. (2019a). doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). 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). 1862, 324334. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Am. Biol. Adv. (2012). Arch. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 27, 441450. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. Dermatol. 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). 26, 524540. Foster, J. 289, 1005710068. Biochimie 86, 173178. 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). Trends Biotechnol. Micron 32, 185200. Stages of hierarchical assembly of elastic fibers. 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). Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). (2019). They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. Computational smart polymer design based on elastin protein mutability. Developing elastic tissue. 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. 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). (2017). Biophys. 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. (1995). 38, 280291. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Today Biol. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Imaging 11:e007303. J. Biol. A., Torres, A. R., Alvarez, V. L., and Janata, J. 280, 4093940947. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. 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. doi: 10.1016/j.ajhg.2009.09.013. doi: 10.1073/pnas.1014280108. Possible role in nucleated assembly. With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. Tropoelastin #5052. Solving tropoelastins global structure (Baldock et al., 2011) allowed for 3D mapping on tropoelastin of the approximate locations of domains 10, 19, and 25, which were the first unequivocally cross-linked domains to be discovered (Brown-Augsburger et al., 1995). Fabricating organized elastin in vascular grafts. Biotechnol. Genet. 28, 379382. 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). 15, 786801. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Tropoelastin is a flexible molecule that retains its canonical shape. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Studies on the reduction of elastin. Primary structure of porcine tropoelastin. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Elastagen's technology is based on human tropoelastin . 282, 1248412491. Fluor: Q4 Earnings Snapshot | AP News U.S.A. 112, E4408E4415. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. Front. No use, distribution or reproduction is permitted which does not comply with these terms. 34, 8190. Biopolymers 107:e23007. Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. 98, 416. Adv. 41, 494497. This temperature is also known as the transition temperature. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. 293, 1510715119. Human ELN gives rise to a broad variety of splice isoforms, with alternative splicing being observed with exons 22, 23, 24, 26A, 32, and 33 (Fazio et al., 1988; Parks et al., 1992) that result in 13 known human isoforms of the mature tropoelastin protein (Reichheld et al., 2019). Chem. Pharm. Tropoelastin: a novel marker for plaque progression and instability. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Crosslinking [ edit] Detailed Description: Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. Differential expression of two tropoelastin genes in zebrafish. Biochim. Matrix Biol. Structure 14, 16671676. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. Res. (2015). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Hydrophobic domains of human tropoelastin interact in a context-dependent manner. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. 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). Allergan Snaps Up Sydney Biotech for Upfront Payment of US $95M While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . 396, 870873. Sci. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. 68, 411419. Natl. A., Gray, W. R., and Franzblau, C. (1973). The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. Integrins are a major class of cell surface receptor family, of which tropoelastin has been found to interact with two types: v3 (Rodgers and Weiss, 2004) and v5. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. 289, 14671477. II. The full-atomistic model of tropoelastin was developed based on replica exchange molecular dynamics (REMD) simulations, an accelerated sampling method for molecular dynamics (Tarakanova et al., 2018). Matrix Biol. 9:eaai7466. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Elastin, arterial mechanics, and cardiovascular disease Lysinonorleucine. 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). U.S.A. 84, 56805684. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. 220, 312324. These ordered structures can include -helices and -structures (Vrhovski et al., 1997), which depend on the amino acid content and arrangement of domains (He et al., 2012; Reichheld et al., 2014, 2017; Muiznieks et al., 2015) and the choice of solvent (Reiersen and Rees, 2000; Muiznieks et al., 2015). Chem. Eng. Mater. Elastin synthesis and fiber assembly. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Matrix Biol. 58, 270277. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Natl. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). 260, 32553258. 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). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. (2009). The liquid structure of elastin. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). Sci. Thus, at lower temperatures, the water surrounding these domains forms ordered, clathrate-like shells that prevent aggregation until the appropriate temperature is reached (Wu and Weiss, 1999; Miao et al., 2003; Dandurand et al., 2015). 278, 1849118498. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. To get started with texting, you will need: Your phone number 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]. A., Starcher, B. C., and Urry, D. W. (1974). For example, models involving single point mutations at negatively charged residues demonstrated both regional and global destabilization of tropoelastins structure, which were validated by SAXS structures (Yeo et al., 2012; Tarakanova et al., 2018). The N-terminal head caps an extended coil region that consists of domains 218. Matrix Biol. Remodelling the extracellular matrix in development and disease. Sci. 280, 3052630537. Med. Collapse Section. Bioeng. Proc. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. 167, 94103. 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: 10.1021/bi981641y, Kozel, B. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Thus, elastin is responsible, in great part, for the properties of elastic fibers. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. J. Biol. J. Exp. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. Implications for tissue specificity and durability of elastic tissue. Acad. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). 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. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. J. eLife 6:e26526. doi: 10.1111/j.1749-6632.1991.tb17013.x, Mecham, R. P., Levy, B. D., Morris, S. L., Madaras, J. G., and Wrenn, D. S. (1985). Figure 1. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. The alignment of the tropoelastin aggregates .