Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. (2018). (1989). Elastin, arterial mechanics, and cardiovascular disease doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Scientists find way to heal scars left behind by heart attacks Fell muir lecture: collagen fibril formation in vitro and in vivo. Biochemistry 52, 77317741. 69, 89102. U.S.A. 115, 73387343. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Proc. Acad. No use, distribution or reproduction is permitted which does not comply with these terms. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Sci. Modeling has been verified using wet-bench methodologies, forming a robust suite of complementary methodologies that will undoubtedly become more prevalent for exploring the assembly of biological fibers over time. J. Biochem. 149, 282289. 68, 411419. It has become increasingly evident that tropoelastins sequence, structure and subsequent functionality are in a delicate balance; thus, perturbations to tropoelastins sequence can have far-reaching consequences for self-assembly and the resultant architecture of elastic fibers. J. Biol. 1862, 324334. Cardiovasc. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. Calorim. Matrix Biol. 281, 2375723765. Biochemistry of tropoelastin. Partridge, S. M. (1966). A., Gray, W. R., and Franzblau, C. (1973). Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. 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. February 14, 2018 Michael Patrini. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. 275, 2844928454. On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Acta Biomater. 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,". doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. 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). Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. 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 . Acad. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. 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). (2008). 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. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. 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). doi: 10.1002/chem.200305661. Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. Self-healing and thermoreversible rubber from supramolecular assembly. Chem. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Cell Biol. Similarly, a mutation model associated with cutis laxa, or loose skin disease (Hu et al., 2006), was found to exhibit higher stability compared with the wild-type molecule due to the increased longevity of its salt bridges (Hu et al., 2006; Tarakanova et al., 2018). 3, 4 Elastin has a very low rate of turnover, so it . J. Hum. US8974803B2 - Injectable biomaterials - Google Patents The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. The coacervate is made insoluble by irreversible crosslinking. Poly (Val-Gly-Gly-Leu-Gly). Implications for tissue specificity and durability of elastic tissue. 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. 264, 88878891. Biotechnol., 25 February 2021, View all
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. (2018). 289, 14671477. 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. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). Res. Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). Biopolymers 29, 16991706. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. 276, 3603536042. Exp. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. 85, 593605. Natl. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. 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). (2017). Tropoelastins flexibility does not allow it to pack into a crystal lattice and its size renders it too complex to assign atomic interactions using nuclear magnetic resonance (NMR) on a global level (Tamburro et al., 2003, 2006; Bochicchio et al., 2004; Pepe et al., 2008). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 589(19 Pt A), 24772486. 98, 416. Biol. doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). 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). Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. This content is for members only. (2013). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). 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 . U.S.A. 108, 43224327. 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). Mater. Proc. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Indeed, studies examining the consequences of domain insertions and deletions note changes in the intrinsic functionality of tropoelastin, corroborating the hypothesis that domain insertions and deletions result in altered tissue mechanics (Jensen et al., 2000; Kozel et al., 2003; Yeo et al., 2016; Miao et al., 2017). Biochem. Molecular model of human tropoelastin and implications of associated mutations. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. A., and Rucker, R. B. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. doi: 10.1016/s0934-8832(11)80057-0. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Interestingly, the location and orientation of different domains that contacted each other during self-assembly was noted to be heterogeneous, resulting in head-to-head, tail-to-tail, head-to-tail, and lateral interactions (Tarakanova et al., 2019a). 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. 37, 698702. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Eur. 624, 137146. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. (2003). Targeted modulation of tropoelastin structure and assembly. Rush to Beauty Anticipates New Line of Dermal Fillers from Allergan 82, 335340. This deduction has been corroborated by the observation that tropoelastin with multiple allysine modifications displays conformational sampling comparable to that of the wild-type molecule, suggesting it is more likely to readily participate in self-assembly. 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). (2006). Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. 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). CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). J. Biol. Rep. 8, 116. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. J. Biol. Dermatol. The reduction in solvent accessible surface area of the mutant molecules suggests that the underlying mechanism for their altered self-assembly properties observed in experiments is due to less exposure of the appropriate hydrophobic domains required for coacervation. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). 284, 22162230. 33, 54685481. 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. Biochemistry 8, 28372845. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. Sci. Detailed Description: Natl. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. J. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. J. Clin. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. 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. Biochem. Allergan to acquire University of Sydney spinoff Elastagen In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Allergan to Acquire Elastagen to Access Next Generation Injectable Biopolymers 107:e23007. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Cellular expression of tropoelastin mRNA splice variants. J. Mol. 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. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . 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). Elastin: Structure, Function, Skin Care & Supplements - Cleveland Clinic A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With 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). The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). 270, 1777817783. Macromol. Am. eLife 6:e26526. 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. Ann. Tropoelastin undergoes minimal energy loss during extension, similar to other polymers such as rubber and resilin (Elvin et al., 2005; Cordier et al., 2008; Baldock et al., 2011). Healthcare Investment Banking - The Walden Group Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . The hydrophobic domain 26 of human tropoelastin is unstructured in solution. Advanced BioMatrix - Recombinant Tropoelastin, Lyophilized #5052 FEBS J. 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 importance of tropoelastins flexibility during self-assembly has also been examined in the light of natural allysine modifications, which condense to give cross-links within mature elastin (discussed further in the following section) (Ozsvar et al., 2019). Biophys. Sci. Synthesis and properties of crosslinked recombinant pro-resilin. J. Pathol. Elastagens tropoelastin is identical to that present in human tissue, and has many potential clinical applications, including treatment for acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Biosci. doi: 10.1002/bip.1981.360200611. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. J. Biol. 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. The isoform-function theory is further reinforced by the presence of two different ELN genes within teleosts that are differentially expressed both spatially and temporally during development (Miao et al., 2007). (2005). A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed . doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). (1973). 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). Elastin synthesis and fiber assembly. U.S.A. 110, 28522857. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). Mol. Res. Arch. Elastagen has received investment from an international syndicate of venture groups including AmorePacific Ventures, Brandon Capital, Cell Innovation Partners, Cicada Innovations, GBS Ventures, Korea Investment Partners and the Wellcome Trust. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Genet. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. Cell Biol. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). 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). Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Int. U.S.A. 109, 28782883. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. Sci. Biophys. Biotechnol. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. A. doi: 10.1038/nature04085. 28, 432441. 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. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Chemistry 10, 31663176. Biochemistry 42, 1334713362. To get started with texting, you will need: Your phone number Transl. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. 2:e1501145. Four days after a heart attack, purified tropoelastin was injected into the heart. Biophys. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). Baul, U., Bley, M., and Dzubiella, J. 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]. This acquisition and the development of a next generation of injectables based on this technology will ensure Allergan offers innovative filler products for years to come., Robert Daniels, Elastagen CEO, noted: Partnering with Allergan, a leader in medical aesthetics, is incredibly exciting. 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. 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). Genet. 10, 15321541. 25, 10231029. Lysinonorleucine. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Domains 12 to 16 of tropoelastin promote cell attachment and spreading doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Bull. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. The liquid structure of elastin. Cell Physiol. For example, their inclusion in peptides derived from hydrophobic domains confers decreased times taken for self-assembly, most likely due to their favorable interaction with aqueous solvent (Miao et al., 2003). This process is reversible and thermodynamically controlled and does not require protein cleavage. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 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). Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Tropoelastins domains each arise from single exons of the ELN gene. 26, 115124. (2017). doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992).