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). Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. Res. J. Biochem. (2005). (2014). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. A., and Rucker, R. B. Tropoelastin #5052. doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). (2015). Allergan is an industry leader in Open Science,a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. Banded fibers in tropoelastin coacervates at physiological temperatures. 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). 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. Integrins are a major class of cell surface receptor family, of which tropoelastin has been found to interact with two types: v3 (Rodgers and Weiss, 2004) and v5. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 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. (1977). (2011). 26, 115124. 15, 786801. The N-terminal head caps an extended coil region that consists of domains 218. 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). While tropoelastin is a flexible molecule, a combination of optical and structural analyses has defined key regions of the molecule that directly contribute to the elastomeric properties and control the cell interactions of the protein. An electron microscopic study. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. 85, 593605. 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. N. Y. Acad. Mol. Tropoelastin interacts with microfibril components including fibrillin-1, fibulin-4, and -5, and other associated molecules such as latent transforming growth factor binding protein-4 (Visconti et al., 2003; McLaughlin et al., 2006; Urban et al., 2009; Yamauchi et al., 2010; Noda et al., 2013; Lockhart-Cairns et al., 2020). doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. (2006). 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. Eng. Mol. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). The coacervate is made insoluble by irreversible crosslinking. (2015). Albert, E. N. (1972). The conversion of a single lysine to an allysine results in structural stabilization, which may serve as a checkpoint during self-assembly to ensure that molecules incapable of forming multiple cross-links are not incorporated into the growing chain. [Epub ahead of print]. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. Acta Biomater. Parameter, Testing, and Method. 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. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Biotechnol., 25 February 2021, View all 589(19 Pt A), 24772486. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Tropoelastin: a novel marker for plaque progression and instability. Sci. Biol. Acta Histochem. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. FEBS J. Mater. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. The ELN gene provides instructions for making a protein called tropoelastin. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. 275, 2844928454. 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. Biochim. (2020). Chem. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. Micron 32, 185200. (2012). Trends towards maximal association are apparent when each of these parameters is varied. Am. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. 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. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Non-polar residues are a major contributor to protein folding, as their unfavorable interactions with water drive them to bury into the protein core, however, as tropoelastin is comprised of numerous hydrophobic domains, it has been demonstrated that many of these domains will be at least partially solvent exposed (Dyksterhuis et al., 2007). doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Characterization of the complete human elastin gene. Acad. Sci. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). 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. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Biol. 27, 441450. 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). 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). Cell Biol. Biochemistry 42, 1334713362. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). Elastic fibers provide tissues with mechanical resilience, durability, and cell interactivity, which support a diverse range of specialized functionality. Indeed, cryo-EM was recently reported to have a lower molecular size limit of approximately 50 kDa, however, it has not yet been successfully applied to characterize tropoelastin (Murata and Wolf, 2018). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). 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). doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. The hydrophobic domains contain repetitions and variations of Val-Pro-Gly-Val-Gly motifs (Figure 1), resulting in the aforementioned low complexity of sequence (Foster et al., 1973; Gray et al., 1973). (1995). doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). Natl. For more information, visit Elastagens website atwww.elastagen.com. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Additionally, coarse-graining the full-atomistic model has allowed for the examination of mesoscale tropoelastin assembly and, in particular, deciphered the orientation of tropoelastin molecules that occurs during early stage assembly (inset image) (Tarakanova et al., 2019a). doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Biochemistry of tropoelastin. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Chemistry 10, 31663176. 289, 1005710068. J. Biol. Biochim. 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). doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Elastases can be in the form of serine- (e.g., Ela-2), cysteine- (e.g., cathepsin I), or matrix metalloproteinases (MMP-2, -7, -9, and -12), and bioactive peptides include the VGVAPG peptide. 276, 3603536042. 282, 1248412491. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. The liquid structure of elastin. (1973). Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. Elastin is heterogeneously cross-linked. 432, 57365751. Delineation of unusual features in the 5-flanking region. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). 276, 4457544580. FEBS J. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Elastin synthesis during perinatal lung development in the rat. Developing elastic tissue. Studies on the reduction of elastin. Similarly, a mutation model associated with cutis laxa, or loose skin disease (Hu et al., 2006), was found to exhibit higher stability compared with the wild-type molecule due to the increased longevity of its salt bridges (Hu et al., 2006; Tarakanova et al., 2018). Pharmacol. II. Biochemistry 52, 77317741. U.S.A. 115, 73387343. Circ. 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). doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). 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. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. 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). 9:eaai7466. doi: 10.1016/j.ajhg.2009.09.013. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Cell Biol. Allergan's Acquisition of Elastagen. Figure 1. Cell Biol. J. Biol. 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). Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. Proc. Powered by Madgex Job Board Software. Thus, computational approaches can be considered as important means to complement wet bench experiments. 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. 249, 997998. Invest. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Biomacromolecules 18, 599609. Protein Eng. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). Due to the lack of a full-atomistic structure, a number of elastin derivatives, including isolated tropoelastin domains (Toonkool et al., 2001; Mackay et al., 2005; Dyksterhuis et al., 2007; Dyksterhuis and Weiss, 2010) and synthetic elastin-derived peptides (EDPs) (Luan et al., 1990; Tamburro et al., 1992; Kentsis and Sosnick, 1998; Kumashiro et al., 2006; Reichheld et al., 2014, 2017; Muiznieks et al., 2015; MacEwan et al., 2017; Tarakanova et al., 2017) have been studied to understand tropoelastins domain level properties. 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).
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