Tropoelastins primary sequence is low in complexity and contains repetitive motifs. Thus, elastin is responsible, in great part, for the properties of elastic fibers. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. *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. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). (2018). 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. Imaging 11:e007303. Unsubstituted models are also critical to understanding self-assembly. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. (2014). Possible role in nucleated assembly. This canonical computational structure was determined to be highly similar to the envelope found via SAXS/SANS, where both consist of an extended molecular body accompanied by a protruding foot (Baldock et al., 2011). Baul, U., Bley, M., and Dzubiella, J. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. (2018). 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. Unlike hydrophobic domains, cross-linking domains in isolation are unable to self-assemble; thus, they have been studied in the context of the cross-linking of elastin-derived biomaterials (Annabi et al., 2017; Yue et al., 2017). Nature 246, 461466. 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). 43, 131138. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . 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). Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. Proc. Cell Biol. DEERFIELD, IL - Caterpillar Inc. (NYSE: CAT) today announced it will move its global headquarters to the company's existing office in Irving, Texas, from its current location in Deerfield, Illinois. Molecular modeling of protein materials: case study of elastin. Acta Biomater. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. The coacervate is made insoluble by irreversible crosslinking. (2006). J. Therm. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Coacervation of tropoelastin. 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). Acad. 149, 282289. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. doi: 10.1016/j.cis.2010.10.003, Yeo, G. C., Tarakanova, A., Baldock, C., Wise, S. G., Buehler, M. J., and Weiss, A. S. (2016). Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. 150, 154162. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. A., Torres, A. R., Alvarez, V. L., and Janata, J. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. (2015). J. Mol. Chem. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. 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. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. 69, 89102. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. 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, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. Matrix Biol. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). Acta Histochem. Genet. (1973). doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). Proc. Biopolymers 107:e23007. 38, 280291. Sci. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Rep. 8, 116. The ELN gene provides instructions for making a protein called tropoelastin. doi: 10.1038/nature04085. 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). 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). Poly (Val-Gly-Gly-Leu-Gly). 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. (1989). Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. Thus, at lower temperatures, the water surrounding these domains forms ordered, clathrate-like shells that prevent aggregation until the appropriate temperature is reached (Wu and Weiss, 1999; Miao et al., 2003; Dandurand et al., 2015). Dermatol. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). 58, 270277. Stages of hierarchical assembly of elastic fibers. Elastin and other dermal components are gradually lost through aging, sun damage, and following injury, highlighting a need to replace these components to repair the skin. Eng. J. Biochem. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. 19:e1800250. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. For this injection, the researchers used a new . J. Biol. 278, 1849118498. Cell Physiol. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Hogan Lovells represented Elastagen Pty Ltd. on the deal. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. 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. Invest. J. Biol. Natl. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. J. Biol. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). Biol. 27, 441450. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. More recently, it has been demonstrated that KA domains consist of random coil content prior to self-assembly and become more ordered as molecules aggregate, marrying the observations discussed above into a cohesive model within the context of assembly and the requirements of higher-order structures (Reichheld et al., 2014). Chemistry 10, 31663176. 270, 1777817783. Adv. 13, 739743. 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 . Tropoelastin (TE) is the main (>90%) component of elastin, wherein crosslinked assembled coacervates of TE are exposed to lysyl oxidases and interact with microfibrils to expand elastin fibers. Elastin synthesis and fiber assembly. J. Biol. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. Eur. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Proc. Proc. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Biol. [Epub ahead of print]. Acad. Proc. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. Dermatol. Cell Biol. Sci. 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. Biochemistry of tropoelastin. Studies on the reduction of elastin. For more information, visit Elastagens website atwww.elastagen.com. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. 280, 4093940947. 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). Collapse Section. 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). On the cell surface, EBP forms a complex with protective protein/cathepsin A (PPCA) and neuraminidase-1 (Neu-1), giving rise to the ERC (Duca et al., 2007). (2013). The smooth muscle cell. 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). 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. 9:eaai7466. Acad. (1995). Biol. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). Synthesis and properties of crosslinked recombinant pro-resilin. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Chem. Cellular expression of tropoelastin mRNA splice variants. J. Biomol. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. J. Hum. Simul. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Protein Eng. Chem. Eur. 16,17 We have previously shown that monomeric TE is utilized as a substrate by dermal fibroblasts in the formation of elastin fibroblasts in vitro, where For more information, visit Allergans website atwww.Allergan.com. 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. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Nature 437, 9991002. Bioeng. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. (1977). Biopolymers 103, 563573. (2007). 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). Biophys. (1981). 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. J. Biol. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). (2017). Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. 266, 308314. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Structural changes and facilitated association of tropoelastin. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995).
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