Biol. 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. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Mol. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Ann. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). We are making enrolling in text alerts easier than ever. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Molecular docking studies utilizing tropoelastin and the 3D structure of LOX1 (Vallet et al., 2018) may assist in our understanding as to whether the enzyme has a preference for modifying particular tropoelastin residues. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. Trends towards maximal association are apparent when each of these parameters is varied. 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. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. Biotechnol. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). 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. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. No use, distribution or reproduction is permitted which does not comply with these terms. Figure 2. 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). Sci. Natl. Molecular model for elastin structure and function. doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. (2003). Biol. 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). 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). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. J. Biochem. 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. FEBS J. J. Med. Proc. FEBS Lett. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). J. Biol. Characterization of the complete human elastin gene. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). 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. Proc. Free energy determinants of secondary structure formation: I. alpha-Helices. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. 260, 32553258. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. In addition to its involvement in molecular elasticity, the flexibility of tropoelastin also a key requirement for self-assembly into elastin, with mutations that perturb this having detrimental effects on tissue (Yeo et al., 2016, 2017). 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. Further to this, the current model of elastin assembly does not account for how long strings or sheets of tropoelastin are capable of forming spherules on a macroscopic scale (Tu et al., 2010). 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). 282, 1248412491. (1965). 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. (2005). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. Tropoelastin massively associates during coacervation to form quantized protein spheres. Biochim. Ltd., which was sold to Allergan, now a division of AbbVie. 87, 18281834. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). doi: 10.1038/nature06669, Cox, B. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. 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. 82, 335340. Banded fibers in tropoelastin coacervates at physiological temperatures. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. Am. Cell Physiol. The lysines of domain 15 and 17 are believed to play key roles in this interaction. 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. Poly (Val-Gly-Gly-Leu-Gly). Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Bioeng. 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). 33, 54685481. 28, 379382. 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. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). 281, 2375723765. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). Cell Biol. J. Biol. Acad. J. Biol. 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). FEBS J. Rep. 8, 116. J. Biol. Tropoelastin: a novel marker for plaque progression and instability. 270, 1777817783. Package Size. Natl. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. J. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. (2013). Matrix Biol. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. doi: 10.1016/j.biocel.2008.03.017, Wise, S. G., Yeo, G. C., Hiob, M. A., Rnjak-Kovacina, J., Kaplan, D. L., Ng, M. K., et al. (2019). 29, 152159. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). 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). Acad. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. (2015). 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. Fell muir lecture: collagen fibril formation in vitro and in vivo. 220, 312324. Int. Elastin is a critical skin protein consisting of crosslinked 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. Coacervation involves the agglomeration of protein molecules, which is an . 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. 250, 9298. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Matrix Biol. Cell. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. Tropoelastins sequence and domain arrangement. 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). Biol. Delineation of unusual features in the 5-flanking region. Crosslinking [ edit] Possible role in nucleated assembly. Eng. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. Invest. 278, 4855348562. Provides infrastructure for further development and following approval to commercialize Elastagens products, SYDNEY February 7th: Elastagen Pty Limited, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced that it has entered into a definitive agreement under which Allergan, a leading global biopharmaceutical company, has agreed to acquire Elastagen for an upfront payment of US$95M plus contingent, commercial payments.. Domain 26 of tropoelastin plays a dominant role in association by coacervation. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. Nature 451, 977980. 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 . doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. U.S.A. 109, 28782883. doi: 10.1038/nature04085. 624, 137146. (2020). Chem. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). Elastin synthesis in arterial smooth muscle cell culture. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Chem. 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. (2016). Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. 28, 432441. Cell Biol. Thus, computational approaches can be considered as important means to complement wet bench experiments. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). Micron 32, 185200. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. 26, 115124. Chem. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). (2005). February 14, 2018 Michael Patrini. J. Biol. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Self-healing and thermoreversible rubber from supramolecular assembly. Baul, U., Bley, M., and Dzubiella, J. U.S.A. 108, 43224327. Chem. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Fed. doi: 10.1002/chem.200305661. Elastic fibers provide tissues with mechanical resilience, durability, and cell interactivity, which support a diverse range of specialized functionality. J. Biol. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. Thus, elastin is responsible, in great part, for the properties of elastic fibers. 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. doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. J. Clin. J. Biol. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. 149, 282289. I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. 37, 698702. 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. Differential expression of two tropoelastin genes in zebrafish. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). 249, 997998. 43, 131138. Targeted modulation of tropoelastin structure and assembly. More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). Although there is no 3D structure for porcine tropoelastin, porcine tropoelastin differs from that of humans (Sandberg et al., 1977), leaving it unclear as to whether these domains align as expected in human tissue. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. 9:eaai7466. 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). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. Figure 3. Furthermore, tropoelastins hydrophobic and cross-linking domains are arranged in alternating patterns throughout the majority of the molecule, giving rise to both inter- and intra-domain level repetition. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). Biopolymers [Epub ahead of print]. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). The hydrophobic domains vary in length, with the majority of the shorter (95 residues) domains occurring near the N-terminus, while the longer (up to 55 residues) domains are found within tropoelastins central and C-terminal regions (Indik et al., 1989). Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a).
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