Biopolymers 29, 16991706. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. (2018). doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. The ELN gene provides instructions for making a protein called tropoelastin. 3, 4 Elastin has a very low rate of turnover, so it . 275, 2844928454. Lab. Adv. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. 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). (1995). doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). doi: 10.1021/bi981641y, Kozel, B. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. To get started with texting, you will need: Your phone number doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. (2006). doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. FASEB 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. Implications for microfibril and elastic fiber assembly. Further down the molecule, the cell-interactive C-terminus was noted to be highly flexible, indicating that high conformational sampling could be conducive to tropoelastins interactions between cell-surface receptors and elastic fiber-associated proteins. J. Biol. Molecular model of human tropoelastin and implications of associated mutations. Biochemistry 8, 28332837. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. 410, 317323. Figure 2. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. 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). 29, 152159. 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). More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). 289, 489492. 3, 28322844. Biomaterials 139, 163171. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. (2019a). Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. J. Biochem. Plus 2:100002. doi: 10.1016/j.mbplus.2019.03.001, Parks, W. C., Roby, J. D., Wu, L. C., and Grosso, L. E. (1992). 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. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. Synthesis and structural studies of a pentapeptide sequence of elastin. Albert, E. N. (1972). 26, 524540. 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). Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Res. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. J. Biol. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. Acad. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. Tropoelastin: a novel marker for plaque progression and instability. Elastin: molecular description and function. Elastases can be in the form of serine- (e.g., Ela-2), cysteine- (e.g., cathepsin I), or matrix metalloproteinases (MMP-2, -7, -9, and -12), and bioactive peptides include the VGVAPG peptide. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. Earnings, adjusted for non-recurring costs, came . 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 . A comprehensive map of human elastin cross-linking during elastogenesis. Nature 246, 461466. J. Biol. Trends Biotechnol. (2016). J. 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). 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). Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Tropoelastin massively associates during coacervation to form quantized protein spheres. By probing mutations in computational studies that resolve the atomistic structure of the molecule, the deduction of mechanisms associated with changes to functional roles of specific domains has become feasible, and a connection between local structures and biological performance can be established (Figure 2; Tarakanova et al., 2018). Biol. Trends Biotechnol. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Rep. 8, 116. (1995). Pathol. 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). (2014). Modeling utilizing tropoelastin derivatives has demonstrated that structural compaction into both coils and globules occurs above the transition temperature of self-assembly, which may assist in explaining the anisotropic nature of mature elastin (Baul et al., 2020). 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). Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Exp. Tropoelastin #5052. Targeted modulation of tropoelastin structure and assembly. Isolation and characterization of crosslinked peptides from elastin. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. 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. AW gratefully acknowledges NHMRC funding (Ref: 1195827). Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Chem. Acta 303, 363369. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). It is likely that, as a general rule, integrin binding to tropoelastin is mediated via GAGs, which is facilitated by the repetition of tropoelastins primary sequence and the surface exposure of positively charged similar domains (Lee et al., 2017; Bochicchio et al., 2021). Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Intracellularly, EBP is associated with tropoelastin after the release of the signal peptide and acts as a chaperone to prevent self-aggregation and proteolysis as it transported to the cell membrane, after which EBP is then recycled and serves as a reusable shuttle protein (Hinek et al., 1995). Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . Biotechnol. 79, 277284. doi: 10.1016/s0021-9258(19)83613-x, Miao, M., Bellingham, C. M., Stahl, R. J., Sitarz, E. E., Lane, C. J., and Keeley, F. W. (2003). doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. (2003). doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. 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). FEBS Lett. *Correspondence: Anthony S. Weiss, tony.weiss@sydney.edu.au, These authors have contributed equally to this work, Fibrous Assemblies: From Synthesis and Nanostructure Characterization to Materials Development and Application, Front. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. (2018). Cell Biol. Cell Biol. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Elastin synthesis in arterial smooth muscle cell culture. 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. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. [Epub ahead of print]. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. Thus, computational approaches can be considered as important means to complement wet bench experiments. 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). Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Biochemistry of tropoelastin. AW is the Scientific Founder of Elastagen Pty. Biomed. Interactions with these integrins on the surface of mesenchymal stem cells, either through surface bound or as soluble tropoelastin, promote MSC proliferation and phenotypic maintenance via FAK and PKB/AKT (Yeo and Weiss, 2019). Fibrillin-1 interactions with heparin. Sci. Natl. Biomacromolecules 18, 599609. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. 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.. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. Elastin is one of the most abundant proteins in your body. Rev. Crosslinking [ edit] Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). 149, 282289. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). Exp. (2001). Chem. (2015). Int. (1989). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. U.S.A. 112, E4408E4415. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. Chem. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. 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. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Biophys. Partridge, S. M. (1966). 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. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. Sci. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. 207, 8796. 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. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Matrix Biol. 1862, 324334. doi: 10.1038/nature06669, Cox, B. U.S.A. 108, 43224327. Protein Eng. Mol. J. Biochem. Self-healing and thermoreversible rubber from supramolecular assembly. 300, 13351359. (2018). (2005). 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. 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). (2012). Biomacromolecules 20, 11781189. Specific instructions are found in the Directions for Use. Water structure and elastin-like peptide aggregation. Cytochem. 167, 94103. Elastogenesis in human aorta: an electron microscopic study. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. The coacervate is made insoluble by irreversible crosslinking. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. 19:e1800250. (2005). For more information, visit Elastagens website atwww.elastagen.com. Matrix Biol. Pathol. 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). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. 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). Adv. 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). 270, 1777817783. No use, distribution or reproduction is permitted which does not comply with these terms. 10, 15321541. Acta 761, 1722. Chem. Approximately 90% of tropoelastins lysines undergo modification and/or participate in cross-links, indicating that mature elastin is extensively cross-linked (Kozel et al., 2003; Schmelzer et al., 2019). Cell Res. 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. J. Biol. Parameter, Testing, and Method. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). J. Biochem. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. 276, 4457544580. J. Clin. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. 280, 3052630537. Figure 1. 13, 739743. U.S.A. 84, 56805684. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. Natl. doi: 10.1073/pnas.1014280108. U.S.A. 115, 73387343. Modulative effects are also observed within full length tropoelastin, where disruptions to domain 26 diminish self-assembly (Jensen et al., 2000), highlighting the context of primary sequence on higher order structures. Biol. Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Acta Gen. Subj. (2017). doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Figure 3. 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). (2008). A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. J. J. Mol. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). February 14, 2018 Michael Patrini. Calorim. Chem. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Hydrophobic domains of human tropoelastin interact in a context-dependent manner. Biochim. 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. J. Biomol. Domain 36 of tropoelastin in elastic fiber formation. EBP plays two roles in the assembly of elastin. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Natl. Developing elastic tissue. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. 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). Foster, J. (2019). Biochemistry 52, 77317741. Front. Biol. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. 25, 10231029. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss.