Nature 246, 461466. Front. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). 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). 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). Collapse Section. Parameter, Testing, and Method. Pediatr. Proc. Front. 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). 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. Chemistry 10, 31663176. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Biomaterials 139, 163171. 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). doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). (2018). The authors wrote and submitted this manuscript in response to an invitation by the Editor. FEBS Lett. Proc. (1995). Natl. Tropoelastins hydrophobic domains are predominantly responsible for the random coil content of the monomer, and are the result of the unique pairing of proline and glycine pairs that are interspersed throughout the majority of hydrophobic domains (Rauscher and Pomes, 2017). Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. Pathol. doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). Shape of tropoelastin, the highly extensible protein that - PNAS Elastogenesis in human aorta: an electron microscopic study. The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 278, 4855348562. J. Biochem. Closer to the base of the molecule, the flexible hinge region between domains 21 and 23 presented with a scissors-like bending, which is now believed to contribute to elasticity and multimeric assembly through enhanced conformational space sampling (Tarakanova et al., 2019b). (2006). 280, 4093940947. 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). doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). The compositions include a coalescence-controlling agent in the form of a polysaccharide or polysaccharide derivative, in an amount effective for providing the substance with the properties of flow, enabling injection. doi: 10.1073/pnas.1014280108. 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). AW is the Scientific Founder of Elastagen Pty. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. All authors contributed to writing and editing the review. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With Sci. Proc. Earnings, adjusted for non-recurring costs, came . Natl. The hydrophobic domains vary in length, with the majority of the shorter (95 residues) domains occurring near the N-terminus, while the longer (up to 55 residues) domains are found within tropoelastins central and C-terminal regions (Indik et al., 1989). Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. FEBS J. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. 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: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Package Size. However, there are aspects of this model that warrant further investigation. Mol. (2019a). (2017). Chem. 82, 335340. 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. 43, 131138. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Lyophilized Powder. 25, 10231029. Albert, E. N. (1972). Med. 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.. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Cell Physiol. 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). Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). Poly (Val-Gly-Gly-Leu-Gly). Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Eng. Elastin-like polypeptides as models of intrinsically disordered proteins. Domains 12 to 16 of tropoelastin promote cell attachment and spreading Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. (1965). Biochem. The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). 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). 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). The N-terminal head caps an extended coil region that consists of domains 2-18. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. 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). Mol. February 14, 2018 Michael Patrini. Chem. Biochemistry 37, 1461314622. doi: 10.7554/eLife.26526. Biopolymers 20, 12471260. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Cell Biol. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. 29, 152159. Invest. 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 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). Remodelling the extracellular matrix in development and disease. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. 589(19 Pt A), 24772486. Acad. Delineation of unusual features in the 5-flanking region. 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. Elastin - Wikipedia Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). (2020). The resultant bending motion rather than scissors-twist motion that stemmed from this stabilization highlights the mutants diminished flexibility as a key driver of impaired fiber assembly in cutis laxa (Tarakanova et al., 2018). doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 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). *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. doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Biotechnol., 25 February 2021, View all Adv. This content is for members only. (2020). 4, 508524. U.S.A. 84, 56805684. 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. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. U.S.A. 110, 28522857. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. The ELN gene provides instructions for making a protein called tropoelastin. [Epub ahead of print]. 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). Micron 41, 268272. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. 15, 786801. The alignment of the tropoelastin aggregates . With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Sci. 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. Hogan Lovells represented Elastagen Pty Ltd. on the deal. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). U.S.A. 112, E4408E4415. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. (2011). Tropoelastin | Circulation: Cardiovascular Imaging Chem. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. 3, 28322844. Tropoelastins sequence and domain arrangement. J. Biochem. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. 11 Articles, This article is part of the Research Topic, Tropoelastin-Cell Receptor Interactions and Implications for Assembly, https://doi.org/10.3389/fbioe.2021.643110, Creative Commons Attribution License (CC BY).
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