Biochemistry 36, 84138421. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Powered by Madgex Job Board Software. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. (2017). Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Hogan Lovells represented Elastagen Pty Ltd. on the deal. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Unsubstituted models are also critical to understanding self-assembly. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. (2019). Sci. 396, 870873. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Genet. 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. J. Ultrastruct. Biomacromolecules 20, 11781189. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). 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. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). J. Biol. Elastin is a critical skin protein consisting of crosslinked tropoelastin. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. 207, 8796. 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 . Poly (Val-Gly-Gly-Leu-Gly). doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Biomaterials 139, 163171. 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). Biomed. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). 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). 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. Tropoelastins domains each arise from single exons of the ELN gene. (2007). Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. Nature 437, 9991002. Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). Int. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). Structural changes and facilitated association of tropoelastin. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. Am. For example, their inclusion in peptides derived from hydrophobic domains confers decreased times taken for self-assembly, most likely due to their favorable interaction with aqueous solvent (Miao et al., 2003). (2020). doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Imaging 11:e007303. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . Biomacromolecules 18, 599609. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). (2020). Natl. Biosci. Mater. 1862, 324334. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Elastogenesis in human aorta: an electron microscopic study. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). Sci. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. J. Biol. Cell Biol. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. into 200 nm then 12 m spherules, which eventually grow and stabilize into spherules 26 m in diameter (Clarke et al., 2006; Kozel et al., 2006; Tu and Weiss, 2010; Tu et al., 2010). doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). 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. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. (1981). Arch. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. (1977). The last 17 amino acid residues of the C-terminus of domain 36 are also implicated in HS interactions; the last four residues are Arg-Lys-Arg-Lys and are positively charged at physiological pH which provides a charged cluster capable of binding negatively charged HS (Broekelmann et al., 2005). Acad. Synthesis and properties of crosslinked recombinant pro-resilin. 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. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. Tropoelastins sequence and domain arrangement. Fed. Genet. Synthesis and structural studies of a pentapeptide sequence of elastin. 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). Med. A., Gray, W. R., and Franzblau, C. (1973). Biotechnol. doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Med. LOX and LOXL convert the -amino group of lysine to -aminoadipic acid -semialdehyde (allysine) (Schmelzer et al., 2019), which spontaneously undergo either a Schiff base reaction with a lysine, or two allysines crosslink through aldol condensation, to give rise to bifunctional crosslinks (Franzblau et al., 1969; Lent et al., 1969). Co-author Professor Anthony Weiss from the Charles Perkins Centre and Faculty of Science explained: "Tropoelastin can repair the heart because it is a precise replica of the body's natural elastic protein,". doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Matrix Biol. Chem. J. Med. Identification of an elastin cross-linking domain that joins three peptide chains. Biochemistry 45, 95189530. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Biophys. 27, 441450. III. Remodelling the extracellular matrix in development and disease. Acad. 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. J. Biol. Assembly proceeds from a nucleation event and undergoes elongation in a step-wise manner to form a multimer which can occur in a head-to-tail fashion (Wise et al., 2014). (2019). Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. (1965). Direct observation of structure and dynamics during phase separation of an elastomeric protein. (2013). Lysinonorleucine. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Tropoelastin has a defined shape in solution but paradoxically also displays a large percentage of flexible, disordered regions needed for molecular elasticity (4, 5).The tertiary structure of human tropoelastin represents an ensemble of elastic conformers (3, 6), yet occasional conserved sequence elements hint at requirements for functional demands in one or more key parts of this molecule (7 . Colloid Interface Sci. J. Biol. Studies on the reduction of elastin. To get started with texting, you will need: Your phone number Coacervation involves the agglomeration of protein molecules, which is an . Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Biopolymers [Epub ahead of print]. doi: 10.1021/bi981641y, Kozel, B. 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). Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. Biochim. A., and Rucker, R. B. Sci. Chem. Cross-linking domains can be subdivided into KP or KA domains, which denote the amino acids (proline or alanine, respectively) that are adjacent to the lysines (Figure 1). Elastin is heterogeneously cross-linked. Matrix Biol. However, higher resolution data were required to map out its elusive properties and performance within a hierarchical assembly (Tarakanova et al., 2018; Ozsvar et al., 2019). doi: 10.1002/chem.200305661. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. doi: 10.1002/bip.1981.360200611. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. Coacervation of tropoelastin. Earnings, adjusted for non-recurring costs, came . Eur. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). Simul. Circ. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. 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. Matrix Biol. J. Biol. 9:643110. doi: 10.3389/fbioe.2021.643110. 85, 593605. 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). Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Biochemistry 45, 99899996. Sci. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. 260, 32553258. Biopolymers 29, 16991706. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. U.S.A. 112, E4408E4415. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. J. Biochem. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. The human ELN gene is located on the long arm of chromosome 7q11.2 and comprises of 34 exons nestled between lengthy introns (Indik et al., 1987, 1989; Bashir et al., 1989). Free energy determinants of secondary structure formation: I. alpha-Helices. 252, 351365. Sci. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. Matrix 12, 156162. Chem. The liquid structure of elastin. 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). Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. 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. 120, 419426. 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). Fell muir lecture: collagen fibril formation in vitro and in vivo. Nature 451, 977980. 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). Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. 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. 432, 57365751. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Mater. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Pathol. Tropoelastin: a novel marker for plaque progression and instability. Biochemistry 37, 1461314622. It has been postulated that the interaction between tropoelastin and cell surface proteoglycans is part of the assembly process of elastin before it is deposited on microfibrils. Acta 761, 1722. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. 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/s0021-9258(19)83613-x, Miao, M., Bellingham, C. M., Stahl, R. J., Sitarz, E. E., Lane, C. J., and Keeley, F. W. (2003). doi: 10.1038/nature04085. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Lab. (2015). Mater. (2016). Form. Acta Histochem. 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). Cardiovasc. Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. 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. Differential expression of two tropoelastin genes in zebrafish. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Elastin synthesis and fiber assembly. Structure 14, 16671676. Pharm. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Molecular model for elastin structure and function. Pathol. (2017). (2018). 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. 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). 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). Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). J. Pathol. 3, 4 Elastin has a very low rate of turnover, so it .
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