J. Biol. 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,". 7:32. doi: 10.3389/fphar.2016.00032, Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M. P., Jowitt, T. A., Marchand, M. F., et al. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. 282, 1248412491. J. Hum. Elastagen Pty Ltd, 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 plc, a leading global biopharmaceutical company, has agreed to acquire Elastagen. 41, 494497. Pediatr. doi: 10.1016/j.ajhg.2009.09.013. U.S.A. 108, 43224327. For many years it was difficult to study tropoelastin at an atomic scale, but the application of computational methods, such as full-atomistic molecular dynamics and elastic network models, in combination with powerful low-resolution structural studies, have expanded the field and delivered an enhanced understanding of the mechanisms that contribute to self-assembly. J. Biol. 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). This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Acta Histochem. 33, 54685481. Cross-linking requires the modification of at least one of the lysine participants by a member of the copper-containing LOX or lysine oxidase-like (LOXL) enzyme families. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. 82, 335340. Cell Biol. 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). Biotechnol. Assembly proceeds from a nucleation event and undergoes elongation in a step-wise manner to form a multimer which can occur in a head-to-tail fashion (Wise et al., 2014). doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). 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). 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. U.S.A. 84, 56805684. Figure 2. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). J. Biochem. (2012). Fibulin-4 and -5, but not fibulin-2, are associated with tropoelastin deposition in elastin-producing cell culture. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. 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). 26, 17001709. doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). Sci. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right. Biochemistry 8, 28372845. Elastin synthesis in arterial smooth muscle cell culture. 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. 1862, 324334. Nature 246, 461466. The authors wrote and submitted this manuscript in response to an invitation by the Editor. U.S.A. 115, 73387343. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Res. Exp. A., and Rucker, R. B. 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). Characterization of the complete human elastin gene. This model revealed that tropoelastin maintains a canonical or average structure based on the distribution of its possible conformations in spite of its flexible nature (Figure 2), as well as the possible roles that local structures play in biological processes, specifically, elastogenesis (Tarakanova et al., 2019b). Cell Biol. All authors contributed to writing and editing the review. Int. The coacervate is made insoluble by irreversible crosslinking. Crosslinking [ edit] (2006). Acta Gen. Subj. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). Invest. It has recently been suggested that fibrillins are capable of stabilizing tropoelastin, possibly for the purpose of selecting conformations that are favorable for elastin assembly (Lockhart-Cairns et al., 2020). J. Biol. 276, 3603536042. Front. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. (2012). 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. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Acad. Biol. Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Matrix Biol. 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. Acad. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. (2017). Cardiovasc. Albert, E. N. (1972). 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). Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Anal. Cellular expression of tropoelastin mRNA splice variants. 300, 13351359. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. 28, 432441. Fibrillin-1 interactions with heparin. J. Mol. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. Acta Biomater. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Acad. Elastogenesis in human aorta: an electron microscopic study. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. (2019b). Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. 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). doi: 10.1016/j.biomaterials.2017.04.050, Keywords: elastin, elastic fibers, tropoelastin, computational modeling, assembly, Citation: Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A and Weiss AS (2021) Tropoelastin and Elastin Assembly. Biol. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. Matrix Biol. Biomed. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). 252, 351365. Synthesis and structural studies of a pentapeptide sequence of elastin. (1965). Biopolymers 20, 12471260. Coacervation of tropoelastin. J. Biol. J. Biol. Chem. 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. 10, 15321541. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. 249, 997998. 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). 84, 6880. 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). In addition to its involvement in molecular elasticity, the flexibility of tropoelastin also a key requirement for self-assembly into elastin, with mutations that perturb this having detrimental effects on tissue (Yeo et al., 2016, 2017). Biol. Domain 36 of tropoelastin in elastic fiber formation. Sci. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Coacervation characteristics of recombinant human tropoelastin. 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. Targeted modulation of tropoelastin structure and assembly. Biochim. Proc. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. Differential expression of two tropoelastin genes in zebrafish. Elastagens 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. 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). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. Imaging 11:e007303. B., Broekelmann, T. J., et al. Elastin is heterogeneously cross-linked. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. Rev. Elastin: molecular description and function. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. 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. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Model. A comprehensive map of human elastin cross-linking during elastogenesis. 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). doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). (1988). Free energy determinants of secondary structure formation: I. alpha-Helices. Pharm. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Powered by Madgex Job Board Software. Matrix Biol. Micron 41, 268272. 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). Studies on the reduction of elastin. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). Chem. Tropoelastin: a versatile, bioactive assembly module. 9:643110. doi: 10.3389/fbioe.2021.643110. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). 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). (2005). Stages of hierarchical assembly of elastic fibers. J. Mol. Biochim. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Foster, J. 149, 282289. 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. To get started with texting, you will need: Your phone number Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. 98, 416. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Res. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). (2020). Fed. Simul. (2019). Eng. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. 289, 14671477. Allergan is an industry leader in Open Science,a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). 624, 137146. J. Biomol. Sci. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. Cell Biol. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). 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).
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