281, 2375723765. Healthcare Investment Banking - The Walden Group Aaron, B., and Gosline, J. Biol. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. For more information, visit Allergans website atwww.Allergan.com. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Am. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Elastin: Structure, Function, Skin Care & Supplements - Cleveland Clinic Although alanine tracts within other proteins are predisposed to -helix formation (Yang and Honig, 1995; Avbelj, 2000), high helical content within tropoelastins KA domains was primarily demonstrated to persist in solvents that stabilize secondary structure, such as trifluoroethanol, rather than aqueous solution (Luo and Baldwin, 1997; Tamburro et al., 2006). 10, 441454. (1965). Genet. J. Biomol. Clinical Relevance of Elastin in the Structure and Function of Skin J. U.S.A. 112, E4408E4415. 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). doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). Albert, E. N. (1972). Elastin-like polypeptides as models of intrinsically disordered proteins. A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With All rights reserved. Furthermore, as integrins are involved in the remodeling of the ECM (Bonnans et al., 2014), this is consistent with a model where the tropoelastin-integrin interaction forms part of the wound repair process. 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). A., Starcher, B. C., and Urry, D. W. (1974). 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. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. J. Biol. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. Molecular model of human tropoelastin and implications of associated mutations. 150, 154162. Matrix Biol. Biochemistry 8, 28372845. 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. Acad. Sci. 278, 4855348562. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . After a period of collaboration with the Elastagen team, US biopharmaceutical giant Allergan acquired Elastagen in 2018 for over $350 million in total deal value. 34, 8190. 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. A model two-component system for studying the architecture of elastin assembly in vitro. 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. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. J. Biochem. Proc. (2017). Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. 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. Natl. 250, 9298. (1995). 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 . Biochim. The coacervate is made insoluble by irreversible crosslinking. Stiffness within the context of self-assembly has also been examined with both coarse grained and full-atomistic simulations using polypeptides derived from tropoelastins hydrophobic domains. Interactions with these integrins on the surface of mesenchymal stem cells, either through surface bound or as soluble tropoelastin, promote MSC proliferation and phenotypic maintenance via FAK and PKB/AKT (Yeo and Weiss, 2019). 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. Tropoelastin massively associates during coacervation to form quantized protein spheres. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). Biophys. J. Biol. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. 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. Modeling utilizing tropoelastin derivatives has demonstrated that structural compaction into both coils and globules occurs above the transition temperature of self-assembly, which may assist in explaining the anisotropic nature of mature elastin (Baul et al., 2020). AW is the Scientific Founder of Elastagen Pty. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). Biochem. Approximately 90% of tropoelastins lysines undergo modification and/or participate in cross-links, indicating that mature elastin is extensively cross-linked (Kozel et al., 2003; Schmelzer et al., 2019). Biochim. 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]. Am. Biomacromolecules 18, 599609. Direct observation of structure and dynamics during phase separation of an elastomeric protein. For this injection, the researchers used a new . Genet. Allergan Highlights Key Growth Drivers for Medical Aesthetics Matrix Biol. J. Biochem. Computational smart polymer design based on elastin protein mutability. Frontiers | Tropoelastin and Elastin Assembly doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. A., Torres, A. R., Alvarez, V. L., and Janata, J. Acta Gen. Subj. Conformational transitions of the cross-linking domains of elastin during self-assembly. Cell Biol. Chem. Lab. Hydrophobic domains of human tropoelastin interact in a context-dependent manner. Exp. Acta Biomater. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). 432, 57365751. 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). These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). 282, 1248412491. 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Targeted modulation of tropoelastin structure and assembly. Fluor: Q4 Earnings Snapshot. Matrix Biol. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. Baul, U., Bley, M., and Dzubiella, J. Mater. Shape of tropoelastin, the highly extensible protein that - PNAS 26, 524540. 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). doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. 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 tropoelastin that Elastagen manufactures is an identical copy of what naturally occurs in human tissue, meaning the clinical application opportunities for this has tremendous potential . Res. doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. 9:643110. doi: 10.3389/fbioe.2021.643110. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . 85, 593605. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. FEBS J. ACS Biomater. Natl. Advanced BioMatrix - Recombinant Tropoelastin, Lyophilized #5052 Tropoelastin | Circulation: Cardiovascular Imaging Isolation and characterization of crosslinked peptides from elastin. (2006). (2008). Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Specific instructions are found in the Directions for Use. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. Biosci. The alignment of the tropoelastin aggregates . 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. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). 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). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. This phenomenon is supported by in vitro peptide studies, which note that increasing the space between PG motifs or removing prolines results in more ordered structures (Rauscher et al., 2006). 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). 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). Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Soluble matrix protein is a potent modulator of mesenchymal stem cell Pediatr. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 29, 152159. J. Mol. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. FEBS J. 25, 10231029. Characterization of the complete human elastin gene. Pharm. Variations in the relative abundance of alternatively spliced ELN mRNA transcripts have been observed between tissues, and this diversity is thought to be necessary for the fine tuning of the mechanical characteristics of tissues to suit their unique functional requirements (Reichheld et al., 2019). 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). doi: 10.1073/pnas.1014280108. Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. 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). 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. 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). doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. Nature 437, 9991002. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Circ. 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. 589(19 Pt A), 24772486. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. 31, 261272. Allergan to acquire Australian biotech company Elastagen 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). doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Med. Lyophilized Powder. More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). Detailed Description: J. Biol. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Meanwhile, modifications to the full-atomistic model have revealed the mechanisms that contribute to aberrant fiber structure (Tarakanova et al., 2018) that have been hypothesized to predispose patients to diseases such as acquired cutis laxa (Hu et al., 2006). The hydrophobic domains have been extensively studied and are responsible for facilitating tropoelastins ability to self-assemble (Vrhovski et al., 1997; Toonkool et al., 2001). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Proc. 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. 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. Anal. doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. 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. Biophys. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. Figure 2. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. Macromol. 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). 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: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. doi: 10.1016/j.matbio.2007.05.005, He, D., Miao, M., Sitarz, E. E., Muiznieks, L. D., Reichheld, S., Stahl, R. J., et al. Biopolymers 20, 12471260. 84, 6880. doi: 10.1038/nature06669, Cox, B. The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). Tropoelastin is typically used as a thin coating on tissue culture surfaces. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Cell Physiol. 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). Elastin - Wikipedia Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. 280, 3052630537. Struct. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). Mol. (1987). In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. (1983). Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Natl. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Sci. Elastin is one of the most abundant proteins in your body. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. This suggests a high level of conformational sampling during this phase of coacervation, indicating that the flexibility of tropoelastin plays a key role in assembly that may persist, to some extent, into later stages of assembly (Reichheld et al., 2020). 286, 35943610. Acad. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Stem cell growth accelerated by tropoelastin protein Acad. Sci. (2013). Tropoelastin - PubMed (1995). I thank my team at the University of Sydney and greatly look forward to seeing our science commercialized by Allergan.. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. CICADA TURNS 20: How synthetic skin biotech Elastagen changed lives Acad. Adv. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Novel Recombinant Tropoelastin Implants Restore Skin - PubMed 28, 379382. Form. Cytochem. Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. Acta Histochem. Plus 2:100002. doi: 10.1016/j.mbplus.2019.03.001, Parks, W. C., Roby, J. D., Wu, L. C., and Grosso, L. E. (1992). The liquid structure of elastin. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Sci. 25, 492504. Allergans success is powered by our global colleagues commitment to being Bold for Life. Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. This process is reversible and thermodynamically controlled and does not require protein cleavage. Int. (1988). (2018). N. Y. Acad. J. Exp. Allergan's Acquisition of Elastagen - Global Legal Chronicle 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. 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). J. Biol. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Am. Matrix Biol. (2020). A., Gray, W. R., and Franzblau, C. (1973). Rev. Nature 451, 977980. Fabricating organized elastin in vascular grafts. Dominant driving factors of assembly were examined, including water, temperature and domain pair orientations. Chem. 289, 489492. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. The importance of tropoelastins flexibility during self-assembly has also been examined in the light of natural allysine modifications, which condense to give cross-links within mature elastin (discussed further in the following section) (Ozsvar et al., 2019).
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