Eng. Biochim. Matrix Biol. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. (2017). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. 289, 489492. J. Biol. Proc. Proc. 167, 94103. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. Water structure and elastin-like peptide aggregation. Proc. 264, 88878891. Elastin: molecular description and function. Invest. 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). 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. 589(19 Pt A), 24772486. Chem. Isolation and characterization of crosslinked peptides from elastin. Biochemistry 45, 99899996. Biol. Acad. Acta Histochem. U.S.A. 109, 28782883. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Aaron, B., and Gosline, J. 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: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Biosci. Domain 26 of tropoelastin plays a dominant role in association by coacervation. J. Biol. 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). 26, 524540. Biomed. Ltd., which was sold to Allergan, now a division of AbbVie. N. Y. Acad. 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. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. 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. 27, 441450. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. 4, 508524. Calorim. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. 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). Molecular modeling of protein materials: case study of elastin. 252, 351365. doi: 10.1073/pnas.1014280108. 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). The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). Furthermore, as integrins are involved in the remodeling of the ECM (Bonnans et al., 2014), this is consistent with a model where the tropoelastin-integrin interaction forms part of the wound repair process. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. 22, 109121. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. Exp. Genet. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Tropoelastins primary sequence is low in complexity and contains repetitive motifs. (2006). 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. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. J. Mol. Biomaterials 127, 4960. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. Fed. 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). Ann. 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 . Biotechnol., 25 February 2021, View all 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. Eur. Arch. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. Natl. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). 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. Int. The amino acid sequence of domain 36 is unique; furthermore, its sequence confers a positively charged C-terminus comprising lysines between positively charged arginines, forming a RKRK sequence (Vrhovski et al., 1997). Eng. Cell Biol. 33, 54685481. 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. Chem. Chem. 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). Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. Acta 303, 363369. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. 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). 280, 3052630537. U.S.A. 110, 28522857. The cross-linking domains are enriched for either Lys-Pro (KP) or Lys-Ala (KA) motifs and form cross-links that link growing tropoelastin chains during elastogenesis; note that exon 6 encodes a KA domain. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. 28, 379382. J. Pathol. (2009). Chem. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Acad. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. J. Therm. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. 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). Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). The alignment of the tropoelastin aggregates . Biochemistry 37, 1461314622. (2003). Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . 87, 18281834. Acta Biomater. Tropoelastin was revealed to be an asymmetric molecule with distinct N- and C-terminal regions that are respectively referred to as the head and foot of the molecule. Specific instructions are found in the Directions for Use. 25, 10231029. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. 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). (1987). Proc. A., Torres, A. R., Alvarez, V. L., and Janata, J. Albert, E. N. (1972). Gene 154, 159166. 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. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. This content is for members only. Soluble matrix protein is a potent modulator of mesenchymal stem cell performance. (1981). 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. Adv. Biol. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. J. Biol. Unsubstituted models are also critical to understanding self-assembly. Combinations of these two amino acids result in domains that undergo rapid conformational sampling (Rauscher and Pomes, 2017), which, if perturbed toward a conformation that gravitate toward stability, will assemble into highly ordered amyloid-like fibrils that are not elastomeric (Rauscher et al., 2006; Roberts et al., 2015). 79, 277284. (1995). (1973). 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. A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. Biophys. 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. (2012). Biol. Bonnans, C., Chou, J., and Werb, Z. 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. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Matrix 12, 156162. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Acad. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. 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). J. Biol. doi: 10.1038/nature06669, Cox, B. Synthesis and properties of crosslinked recombinant pro-resilin. 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. Chem. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Structure 14, 16671676. Studies on the reduction of elastin. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. However, higher resolution data were required to map out its elusive properties and performance within a hierarchical assembly (Tarakanova et al., 2018; Ozsvar et al., 2019). The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. 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). Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. 68, 411419. Matrix Biol. Matrix Biol. 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). With leaps in the improvement of cryogenic electron microscopy to characterize flexible molecules, we predict that this approach will contribute to a deeper understanding of tropoelastin structure and self-assembly in the context of endogenous fiber formation and biomaterials fabrication. Poly (Val-Gly-Gly-Leu-Gly). 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]. Sci. doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. J. Hum. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Partridge, S. M. (1966). Dyn. Chemistry 10, 31663176. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). J. Biol. Stages of hierarchical assembly of elastic fibers. (1965). 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). Cooperativity between the hydrophobic and cross-linking domains of elastin. (2019). 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. Biochim. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 286, 35943610. 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). doi: 10.1038/nature04085. FEBS J. 270, 1777817783. 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,". Conformational transitions of the cross-linking domains of elastin during self-assembly. Coacervation optimally occurs at physiological temperature, however, in vitro coacervation can also occur at lower temperatures depending on experimental conditions and the choice of tropoelastin isoform or derivative (Yeo et al., 2011). Chem. doi: 10.1002/bip.1981.360200611. J. Ultrastruct. Sci. Anal. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Targeted modulation of tropoelastin structure and assembly. Proc. Elastin synthesis in arterial smooth muscle cell culture. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. 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. 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). J. Thus, computational approaches can be considered as important means to complement wet bench experiments. 41, 494497. Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. (2001). 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.