tropoelastin allergan

Allergans success is powered by our global colleagues commitment to being Bold for Life. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. (2014). Biochim. Res. Invest. 3, 4 Elastin has a very low rate of turnover, so it . 98, 416. 28, 379382. FEBS Lett. 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.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Sci. The N-terminal head caps an extended coil region that consists of domains 218. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. 82, 335340. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). (2013). Proc. Tropoelastin #5052. Computational smart polymer design based on elastin protein mutability. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Cooperativity between the hydrophobic and cross-linking domains of elastin. (2003). Implications for tissue specificity and durability of elastic tissue. Acad. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). We are very interested in the blend of biochemistry and cell biology, as well as the tissue engineering and regenerative medicine opportunities provided by this amazing elastic protein. 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 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. Genet. 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). Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. 126, 563574. Int. 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. (2019). The N-terminal head caps an extended coil region that consists of domains 2-18. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. 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. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Protein Eng. Attempts to characterize tropoelastins structure have seen a gradual shift from the belief that tropoelastins domains have fixed structures, to understanding that the majority of its domains are capable of transitioning between random coils and transient ordered structures. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Tropoelastins domains each arise from single exons of the ELN gene. Molecular modeling of protein materials: case study of elastin. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Mol. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. Powered by Madgex Job Board Software. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. Chem. Acta Histochem. Sci. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). 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. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. Biophys. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Ltd., which was sold to Allergan, now a division of AbbVie. Elastin is one of the most abundant proteins in your body. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. Indeed, studies examining the consequences of domain insertions and deletions note changes in the intrinsic functionality of tropoelastin, corroborating the hypothesis that domain insertions and deletions result in altered tissue mechanics (Jensen et al., 2000; Kozel et al., 2003; Yeo et al., 2016; Miao et al., 2017). Free energy determinants of secondary structure formation: I. alpha-Helices. Nature 451, 977980. Elastogenesis is the term that collectively describes the hierarchical process of elastic fiber formation, and is comprised of distinct phases: tropoelastin synthesis, coacervation, cross-linking, and deposition. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. Elastin synthesis and fiber assembly. 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). (2012). doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). Sci. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). Rep. 8, 116. 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). Micron 41, 268272. doi: 10.7554/eLife.26526. 278, 1849118498. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Poly (Val-Gly-Gly-Leu-Gly). doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. The lysines of domain 15 and 17 are believed to play key roles in this interaction. Gene 154, 159166. J. (2007). doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). J. Biol. Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). Mater. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. J. Struct. 43, 131138. 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). A model two-component system for studying the architecture of elastin assembly in vitro. Fed. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Biomacromolecules 20, 11781189. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). 85, 593605. 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). Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. N. Y. Acad. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). Acad. Dermatol. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). J. Biol. The advantage of coarse-grained methodologies is that they allow for the simulation of timescales of large molecular systems on the order of microseconds, which are otherwise computationally infeasible with classical full-atomistic molecular dynamics. Primary structure of porcine tropoelastin. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Matrix Biol. 281, 2375723765. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). 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). doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. 33, 54685481. 276, 3603536042. (1989). ACS Biomater. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. Conformational transitions of the cross-linking domains of elastin during self-assembly. Bioeng. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). This process is reversible and thermodynamically controlled and does not require protein cleavage. Tropoelastins sequence and domain arrangement. Cell Biol. Elastin synthesis in arterial smooth muscle cell culture. All rights reserved. II. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. Acad. Sci. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. The smooth muscle cell. Tropoelastin: a novel marker for plaque progression and instability. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. (1983). Circ. This temperature is also known as the transition temperature. 249, 997998. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). Identification of an elastin cross-linking domain that joins three peptide chains. 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). Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). 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). doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Chem. 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. (1987). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Biomaterials 127, 4960. J. Med. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. 37, 698702. 220, 312324. 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). 4, 508524. Tropoelastin undergoes minimal energy loss during extension, similar to other polymers such as rubber and resilin (Elvin et al., 2005; Cordier et al., 2008; Baldock et al., 2011). doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. 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. 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. (2009). Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. 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). Most organisms contain one copy of ELN, other than teleosts and amphibians which notably possess two distinct types of ELN genes (He et al., 2007; Miao et al., 2007, 2009). CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. U.S.A. 108, 43224327. 84, 6880. Studies on the reduction of elastin. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. (2018). Int. J. J. Biol. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). 79, 277284. 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). However, there are aspects of this model that warrant further investigation. 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. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Biopolymers 103, 563573. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. 15, 786801. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. (2021). Collapse Section. doi: 10.1016/j.biomaterials.2017.04.050, Keywords: elastin, elastic fibers, tropoelastin, computational modeling, assembly, Citation: Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A and Weiss AS (2021) Tropoelastin and Elastin Assembly. It is likely that, as a general rule, integrin binding to tropoelastin is mediated via GAGs, which is facilitated by the repetition of tropoelastins primary sequence and the surface exposure of positively charged similar domains (Lee et al., 2017; Bochicchio et al., 2021). (2017). The coacervate is made insoluble by irreversible crosslinking. Molecular dynamics modeling of aggregating tropoelastin-derived peptide chains points to the maintenance of a hydrated, disordered, liquid-like state due to the formation of short-lived inter-chain bonds (Rauscher and Pomes, 2017; Reichheld et al., 2020), mostly likely due to the inducement of random coils by PG repeats (vide supra). Chemistry 10, 31663176. Acta Biomater. 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. Sci. Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. Biochim. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). A., and Rucker, R. B. Structural changes and facilitated association of tropoelastin. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Banded fibers in tropoelastin coacervates at physiological temperatures. (2006). J. Mol. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Acad. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Cell Res. doi: 10.1016/s0934-8832(11)80057-0. Developing elastic tissue. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. (2020). 207, 8796. (2017). Foster, J. Proc. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. J. Mol. Detailed Description: Fibulin-4 and -5, but not fibulin-2, are associated with tropoelastin deposition in elastin-producing cell culture. For example, the highly flexible domains 25 that were noted to generate a twisting motion in N-terminus, were positioned beside domain 6, a relatively immobile region that may assist in stabilizing the subsequent regions. 150, 154162. (2006). Micron 32, 185200. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. doi: 10.1016/j.ajhg.2009.09.013. Biomed. 13, 739743. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. Importantly, the presence of fibrils indicates that the nanostructures formed during initial assembly contribute to the supramolecular structures that arise during both early (spherule) and later (fibril) stages of elastogenesis. 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. (2001). 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. 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. Matrix Biol. Coacervation of tropoelastin. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. Adv. FEBS J. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. Eng. Sci. Model. A comprehensive map of human elastin cross-linking during elastogenesis. Elastin: molecular description and function. The authors wrote and submitted this manuscript in response to an invitation by the Editor. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. Matrix Biol. (1965). Today Biol. 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. J. Biol. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). 275, 2844928454. doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). 26, 17001709. J. Struct. Struct. Rev. Elastin is heterogeneously cross-linked. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. (2012). KA domains were initially thought to form -helices and poly-proline II helices (PPII) due to the presence of cross-links which require a lysine arrangement that was postulated to be achieved via -helical configuration (Brown-Augsburger et al., 1995). Biochemistry 8, 28372845. Investig. Figure 3. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. 410, 317323. 264, 88878891. Fluor: Q4 Earnings Snapshot. doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). 250, 9298. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Exp. 10, 15321541. 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). Proc. Isolation and characterization of crosslinked peptides from elastin. Exp. Figure 2. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. *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. Tropoelastin massively associates during coacervation to form quantized protein spheres. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Its estimated half-life of 70 years (Shapiro et al., 1991) is due to its extensive cross-linking and high hydrophobicity, which render it resistant to degradation (Vrhovski and Weiss, 1998; Schrader et al., 2018; Hedtke et al., 2019).