Proc. Biophys. (2019a). doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). J. Biol. 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). Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Sci. 252, 351365. 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). Cell Res. (2017). Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Biochemistry of tropoelastin. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Arch. 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). Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Bonnans, C., Chou, J., and Werb, Z. Direct observation of structure and dynamics during phase separation of an elastomeric protein. 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 . 25, 10231029. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). 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. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. Genet. 15, 786801. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). (2021). (2018). Chem. Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). 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). Matrix Biol. To get started with texting, you will need: Your phone number eLife 6:e26526. 84, 6880. doi: 10.1111/j.1749-6632.1991.tb17013.x, Mecham, R. P., Levy, B. D., Morris, S. L., Madaras, J. G., and Wrenn, D. S. (1985). U.S.A. 115, 73387343. Elastin synthesis and fiber assembly. 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. (2005). Implications for tissue specificity and durability of elastic tissue. I thank the Elastagen team for their hard work and dedication in developing our innovative tropoelastin product pipeline and look forward to working with Allergan to take these products to market., Commenting on the transaction, Elastagens founding scientist Prof Anthony Weiss added:Our technology has come a long way from the lab bench at the University of Sydney towards developing products for patients around the world. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 276, 4457544580. 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. Tropoelastins domains each arise from single exons of the ELN gene. Eur. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. 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: 10.1016/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. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. 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). EBP plays two roles in the assembly of elastin. However, there are aspects of this model that warrant further investigation. doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. 207, 8796. Biol. 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. Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Proc. (2006). Pathol. Differential expression of two tropoelastin genes in zebrafish. Cell Biol. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. 9:643110. doi: 10.3389/fbioe.2021.643110. 284, 22162230. (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). 126, 283290. A., Starcher, B. C., and Urry, D. W. (1974). (2017). Thus, computational approaches can be considered as important means to complement wet bench experiments. 41, 494497. 85, 593605. (2016). Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Biotechnol. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). 1862, 324334. 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. Tropoelastin: a novel marker for plaque progression and instability. (2006). 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. 264, 88878891. Invest. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Gene 154, 159166. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. Front. 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). For more information, visit Elastagens website atwww.elastagen.com. Acad. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Elastin is heterogeneously cross-linked. 26, 125135. 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. Biochemistry 8, 28372845. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Anal. 282, 1248412491. 280, 3052630537. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Biopolymers 103, 563573. Aaron, B., and Gosline, J. doi: 10.1002/jcp.20546, Kozel, B. 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. J. Biochem. Stages of hierarchical assembly of elastic fibers. 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. 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). 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). Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. (1989). J. Clin. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). 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. The liquid structure of elastin. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. The coacervate is made insoluble by irreversible crosslinking. Cell Biol. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). Such models could be used in conjunction with the full molecular model of tropoelastin to examine the self-assembly of discrete regions to understand the impacts of amino acid substitutions in disease. Biomacromolecules 21, 35233538. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Dermatol. Biomacromolecules 20, 11781189. The N-terminal head caps an extended coil region that consists of domains 2-18. Dermatol. *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. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 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. 266, 308314. 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). The ELN gene provides instructions for making a protein called tropoelastin.