doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). Furthermore, tropoelastins hydrophobic and cross-linking domains are arranged in alternating patterns throughout the majority of the molecule, giving rise to both inter- and intra-domain level repetition. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Matrix Biol. Biopolymers 103, 563573. J. 207, 8796. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. N. Y. Acad. Biochimie 86, 173178. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). Tropoelastin - an overview | ScienceDirect Topics Elastin biomaterials in dermal repair. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Micron 41, 268272. Pathol. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. FASEB J. 25, 492504. Matrix Biol. More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. 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). 276, 4457544580. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). 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). Tropoelastins sequence and domain arrangement. Proc. Matrix Biol. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. 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. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . 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. Matrix Biol. Natl. doi: 10.1002/jcp.20546, Kozel, B. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). J. Struct. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. J. Mol. Matrix Biol. Exp. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. Proc. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. doi: 10.1002/bip.1981.360200611. 396, 870873. (1988). Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. Invest. 13, 739743. By leveraging the advantages of computational models, such as elastic network models, full-atomistic models and coarse grained models, as depicted in Figure 2, the correlation between the structure, motions, and the functionality of tropoelastin have recently been explored in depth (Yeo et al., 2016; Tarakanova et al., 2018, 2019a). The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Aaron, B., and Gosline, J. 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. J. Therm. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). FEBS J. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. 249, 997998. 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. Elastin is one of the most abundant proteins in your body. (1983). Elastin, arterial mechanics, and cardiovascular disease 300, 13351359. 58, 270277. Acta Biomater. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. (2015). Chem. Biol. doi: 10.1016/j.biocel.2008.03.017, Wise, S. G., Yeo, G. C., Hiob, M. A., Rnjak-Kovacina, J., Kaplan, D. L., Ng, M. K., et al. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. 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. (2007). Trends Biotechnol. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). For example, the highly flexible domains 25 that were noted to generate a twisting motion in N-terminus, were positioned beside domain 6, a relatively immobile region that may assist in stabilizing the subsequent regions. Domains 12 to 16 of tropoelastin promote cell attachment and spreading Am. Biol. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. (2005). 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). (2018). Rev. 289, 1005710068. Cell Physiol. 31, 261272. J. Biol. Calorim. 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. (1987). Pharm. Cardiovasc. Mol. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. 150, 154162. J. Biochem. 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). 69, 89102. Figure 2. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). 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). J. Biol. Bonnans, C., Chou, J., and Werb, Z. KA domains were initially thought to form -helices and poly-proline II helices (PPII) due to the presence of cross-links which require a lysine arrangement that was postulated to be achieved via -helical configuration (Brown-Augsburger et al., 1995). This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. Sci. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. The smallest amino acid, glycine is known to promote flexibility within local structures due to lack of steric hindrance, whereas prolines restrictive sidechain inhibits conformational sampling and disrupts the formation of prolonged secondary structures (Roberts et al., 2015). 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. J. Exp. Res. Med. The process of tropoelastin aggregation is initially reversible, as spherules dissipate if the temperature is lowered (Clarke et al., 2006), however, maintenance of a physiological temperature results in maturation, which is indicated by spherule coalescence and the irreversible formation of fibrillar structures (Cox et al., 1974; Bressan et al., 1983; Mithieux et al., 2005). 220, 312324. (1981). Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Front. Even after being able to produce recombinant tropoelastin at scales suited to characterization studies, traditional techniques have not yet produced an experimentally verified atomistic structure (Martin et al., 1995; Tarakanova and Buehler, 2013). Matrix Biol. Pharmacol. 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). 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). 266, 308314. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). J. Biol. Tropoelastin massively associates during coacervation to form quantized protein spheres. U.S.A. 116, 20422051. Chem. Acta Gen. Subj. Chem. The presence of tropoelastin spherules fusing to fibrils has been noted in native tissue, demonstrating marked similarities between in vitro and in vivo coacervation (Haust et al., 1965; Albert, 1972; Kozel et al., 2006). Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). (1989). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Synthesis and properties of crosslinked recombinant pro-resilin. into 200 nm then 12 m spherules, which eventually grow and stabilize into spherules 26 m in diameter (Clarke et al., 2006; Kozel et al., 2006; Tu and Weiss, 2010; Tu et al., 2010). Fed. IRVING, Texas (AP) IRVING, Texas (AP) Fluor Corp. (FLR) on Tuesday reported fourth-quarter net income of $9 million, after reporting a loss in the same period a year earlier. Targeted modulation of tropoelastin structure and assembly. The N-terminal head caps an extended coil region that consists of domains 218. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Production of recombinant human tropoelastin: Characterization and doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. Baul, U., Bley, M., and Dzubiella, J. 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. Sci. Acta 761, 1722. 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). Biomacromolecules 21, 35233538. Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. 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. 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]. Rush to Beauty Anticipates New Line of Dermal Fillers from Allergan Parameter, Testing, and Method. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). J. Struct. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. 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. Acad. 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. Imaging 11:e007303. Biophys. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Biotechnol., 25 February 2021, View all Sci. J. Ultrastruct. 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 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. The majority of tropoelastin synthesis occurs during perinatal development (Myers et al., 1983; Noguchi et al., 1990), however, synthesis may be triggered in response to tissue damage (Parks et al., 1992) or during diseases such as atherosclerosis (Phinikaridou et al., 2018). Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. February 14, 2018 Michael Patrini. Banded fibers in tropoelastin coacervates at physiological temperatures. Biopolymers 107:e23007. Anal. Mater. 29, 152159. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. 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. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Acad. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). 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). doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. 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). (2012). The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. 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).
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