doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). (1965). The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). This suggests a high level of conformational sampling during this phase of coacervation, indicating that the flexibility of tropoelastin plays a key role in assembly that may persist, to some extent, into later stages of assembly (Reichheld et al., 2020). Fibrillin-1 and -2 also interact with proteoglycans (Tiedemann et al., 2001), which coupled with tropoelastin/GAG interactions provide a pathway to the formation of elastic fibers. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. 289, 489492. Domain 36 of tropoelastin in elastic fiber formation. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Sci. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. 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]. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Arch. Moreover, fibulins are essential for elastic fiber directionality, as fibroblasts with fibulin-4 and -5 knockdowns generate poorly formed elastic fibers (Yamauchi et al., 2010), and fibulin-4 / mice display aberrant, poorly cross-linked, and non-fibrous elastin (McLaughlin et al., 2006). Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Communication: coacervation of tropoelastin results in fiber formation. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Elastagen has received investment from an international syndicate of venture groups including AmorePacific Ventures, Brandon Capital, Cell Innovation Partners, Cicada Innovations, GBS Ventures, Korea Investment Partners and the Wellcome Trust. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. 98, 416. Biomaterials 139, 163171. 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). 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. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). J. Mol. 9:643110. doi: 10.3389/fbioe.2021.643110. (1988). Banded fibers in tropoelastin coacervates at physiological temperatures. (2005). doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). Med. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. Allergans success is powered by our global colleagues commitment to being Bold for Life. Sci. 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). 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). 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). The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). 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). Int. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 270, 1777817783. Cell Biol. Biochemistry 45, 99899996. Four days after a heart attack, purified tropoelastin was injected into the heart. (2015). 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). Targeted modulation of tropoelastin structure and assembly. A new amino acid from hydrolysates of elastin. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. IRVING, Texas (AP) IRVING, Texas (AP) Fluor Corp. (FLR) on Tuesday reported fourth-quarter net income of $9 million, after reporting a loss in the same period a year earlier. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Proc. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). An electron microscopic study. J. Hum. Allergan announced that it would be accessing Elastagen's next generation Juvederm dermal filler injectable portfolio, which will now also boast its "key 'youth protein' tropoelastin". 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). J. Biol. Pathol. Chem. 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. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. 26, 115124. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Chem. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Molecular model for elastin structure and function. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. doi: 10.1073/pnas.1014280108. (2018). Tropoelastin has 2 alternating domains: (1) hydrophilic, cross-linked, domains rich in Lys and Ala; and (2) hydrophobic domains (responsible for elasticity) rich in Val, Pro, and Gly, which often occur in repeats of VPGVG or VGGVG. 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). Figure 1. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). (2014). doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). 26, 524540. J. Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Molecular modeling of protein materials: case study of elastin. (2021). Stages of hierarchical assembly of elastic fibers. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). 3, 28322844. J. Biol. 276, 4457544580. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. 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. FEBS J. J. Pathol. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. Elastin biomaterials in dermal repair. Trends Biotechnol. 289, 14671477. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. J. Biochem. Parameter, Testing, and Method. doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Remodelling the extracellular matrix in development and disease. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Acta Biomater. 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). Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . 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). Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. (2019b). J. Biochem. J. Biol. Thus, elastin is responsible, in great part, for the properties of elastic fibers. The ELN gene provides instructions for making a protein called tropoelastin. doi: 10.1016/j.bbrc.2010.05.013, Elvin, C. M., Carr, A. G., Huson, M. G., Maxwell, J. M., Pearson, R. D., Vuocolo, T., et al. Differential expression of two tropoelastin genes in zebrafish. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. 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. Biol. Conformational transitions of the cross-linking domains of elastin during self-assembly. No use, distribution or reproduction is permitted which does not comply with these terms. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Allergan's Acquisition of Elastagen. *Correspondence: Anthony S. Weiss, [email protected], These authors have contributed equally to this work, Fibrous Assemblies: From Synthesis and Nanostructure Characterization to Materials Development and Application, Front. Fibrillin-1 interactions with heparin. Bioeng. 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). (2012).
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