EBP plays two roles in the assembly of elastin. 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. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. We are making enrolling in text alerts easier than ever. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. 220, 312324. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. Simul. Natl. (2014). Acad. 34, 8190. 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). doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). An electron microscopic study. PLoS One 7:e46130. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Gene 154, 159166. 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). This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Sci. 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). Remodelling the extracellular matrix in development and disease. Elastin is heterogeneously cross-linked. doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). 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 review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. Dyn. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. Package Size. Primary structure of porcine tropoelastin. doi: 10.1016/j.matbio.2007.05.005, He, D., Miao, M., Sitarz, E. E., Muiznieks, L. D., Reichheld, S., Stahl, R. J., et al. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. (2016). Earnings, adjusted for non-recurring costs, came . Biosci. 84, 6880. Invest. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). 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). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). 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. Sci. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Molecular modeling of protein materials: case study of elastin. 120, 419426. J. Biol. Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). Cooperativity between the hydrophobic and cross-linking domains of elastin. J. Biol. J. Pathol. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. Figure 2. Elastin synthesis and fiber assembly. A. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Chem. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Albert, E. N. (1972). 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). Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. 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. 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). The liquid structure of elastin. 9:643110. doi: 10.3389/fbioe.2021.643110. On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. Exp. Chem. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Communication: coacervation of tropoelastin results in fiber formation. 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). Proc. Mater. (2006). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Biopolymers 107:e23007. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Cell. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Cytochem. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Biomaterials 139, 163171. Sci. Hogan Lovells represented Elastagen Pty Ltd. on the deal. 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). Coacervation involves the agglomeration of protein molecules, which is an . Eur. J. Biol. 167, 94103. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. In addition to interacting with tropoelastin, fibulin-4 and -5 are capable of also binding LOX and fibrillin-1 and, thus, have key roles in facilitating elastogenesis (Hinderer et al., 2015). 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). Exp. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. 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. 112, E4408E4415. Invest. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). Mol. 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 (). J. Biomol. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Mol. February 14, 2018 Michael Patrini. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. doi: 10.1016/s0934-8832(11)80057-0. The smooth muscle cell. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Arch. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. Human ELN gives rise to a broad variety of splice isoforms, with alternative splicing being observed with exons 22, 23, 24, 26A, 32, and 33 (Fazio et al., 1988; Parks et al., 1992) that result in 13 known human isoforms of the mature tropoelastin protein (Reichheld et al., 2019). Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. (2009). 264, 88878891. Acta Gen. Subj. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. Cell Res. Ltd., which was sold to Allergan, now a division of AbbVie. Bonnans, C., Chou, J., and Werb, Z. Biomed. Med. 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. Cell Biol. 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). Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). All rights reserved. Ann. 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). Biochim. 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). doi: 10.7554/eLife.26526. Dermatol. (1987). doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). (2018). The alignment of the tropoelastin aggregates . (2015). Biochemistry 45, 99899996. Chem. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). 41, 494497. Micron 41, 268272. 25, 10231029. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. A., and Rucker, R. B. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. Sci. 85, 593605. Trends towards maximal association are apparent when each of these parameters is varied. 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: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. 396, 870873. 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). 27, 441450. (2018). Tropoelastin massively associates during coacervation to form quantized protein spheres. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Proc. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Nature 451, 977980. Bioeng. J. Biol. Eur. Implications for microfibril and elastic fiber assembly. Biol. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of 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. Today Biol. Acta Biomater. 68, 411419. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. 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. J. Biol. 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. The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Matrix Biol. Chem. Computational smart polymer design based on elastin protein mutability. Stages of hierarchical assembly of elastic fibers. 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: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Biophys. (2012). To get started with texting, you will need: Your phone number 624, 137146. (2005). Elastin is extensively cross-linked and difficult to break apart into monomers even under harsh conditions, thus, initial strategies included feeding animals a copper deficient diet to prevent lysyl oxidase (LOX) cross-linking of tropoelastin; however, this proved inefficient and time consuming (Wise and Weiss, 2009; Tarakanova et al., 2018). 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). 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). Trends Biotechnol. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. 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. 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. Pharmacol. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Eng. Res. 410, 317323. 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). 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. The N-terminal head caps an extended coil region that consists of domains 2-18. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Tropoelastin, the raw material used to create 'MeTro' elastic surgical glue developed with the University of Sydney, has been found to encourage stem cell growth - with the potential to ultimately help the body repair itself. (2005). Model. We are very interested in the blend of biochemistry and cell biology, as well as the tissue engineering and regenerative medicine opportunities provided by this amazing elastic protein. A series of mapping studies have been recently conducted to pinpoint the locations of these cross-links (Schrader et al., 2018; Hedtke et al., 2019; Schmelzer et al., 2019) as their placements are crucial to understanding the resultant molecular orientation of tropoelastin within cross-linked elastin. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). 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. Natl. (2011). The smallest amino acid, glycine is known to promote flexibility within local structures due to lack of steric hindrance, whereas prolines restrictive sidechain inhibits conformational sampling and disrupts the formation of prolonged secondary structures (Roberts et al., 2015). Genet. 37, 698702. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Collapse Section. 589(19 Pt A), 24772486. Lyophilized Powder. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). Acad. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). 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. Matrix Biol. Parameter, Testing, and Method. 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.

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