Tropoelastin - an overview | ScienceDirect Topics Acta Histochem. J. Biol. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. 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). Biomacromolecules 18, 599609. Protein Eng. 282, 1248412491. Computational smart polymer design based on elastin protein mutability. 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.. Partridge, S. M. (1966). 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. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. Tropoelastin (TE) is the main (>90%) component of elastin, wherein crosslinked assembled coacervates of TE are exposed to lysyl oxidases and interact with microfibrils to expand elastin fibers. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. J. Exp. 28, 379382. The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). A., Gray, W. R., and Franzblau, C. (1973). 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 . 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). *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. Arch. (2019). Cell Biol. Structural changes and facilitated association of tropoelastin. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. 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). Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. J. doi: 10.1002/jcp.20546, Kozel, B. A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. 281, 2375723765. A model two-component system for studying the architecture of elastin assembly in vitro. Coacervation involves the agglomeration of protein molecules, which is an . 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. Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Fluor: Q4 Earnings Snapshot. 220, 312324. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). Int. Biophys. 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. 3, 4 Elastin has a very low rate of turnover, so it . Chem. Banded fibers in tropoelastin coacervates at physiological temperatures. 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. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Coacervation characteristics of recombinant human tropoelastin The ELN gene provides instructions for making a protein called tropoelastin. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. 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. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Biophys. 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. U.S.A. 116, 20422051. 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). 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). Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). 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 scars, stretch marks, aesthetic skin repair and wound repair. A., Starcher, B. C., and Urry, D. W. (1974). 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). J. Med. J. Struct. 264, 88878891. 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). doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). 85, 593605. J. Biochem. Int. Natl. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Biopolymers 20, 12471260. 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. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. (2013). (2020). Bonnans, C., Chou, J., and Werb, Z. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). The alignment of the tropoelastin aggregates . 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). Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. (1995). Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. 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. 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). Nature 437, 9991002. eLife 6:e26526. Subtle balance of tropoelastin molecular shape and flexibility J. Biol. Invest. Pharmacol. The smooth muscle cell. For more information, visit Elastagens website atwww.elastagen.com. Allergan Highlights Key Growth Drivers for Medical Aesthetics Eur. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). Acad. PLoS One 7:e46130. Proc. Matrix Biol. Proc. 13, 739743. 150, 154162. 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. Macromol. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Circ. Model. 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). 25, 492504. doi: 10.1016/j.cis.2010.10.003, Yeo, G. C., Tarakanova, A., Baldock, C., Wise, S. G., Buehler, M. J., and Weiss, A. S. (2016). Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Sci. 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). The authors wrote and submitted this manuscript in response to an invitation by the Editor. 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. 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). In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. Sci. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Free energy determinants of secondary structure formation: I. alpha-Helices. For more information, visit Allergans website atwww.Allergan.com. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). US8974803B2 - Injectable biomaterials - Google Patents U.S.A. 84, 56805684. By probing mutations in computational studies that resolve the atomistic structure of the molecule, the deduction of mechanisms associated with changes to functional roles of specific domains has become feasible, and a connection between local structures and biological performance can be established (Figure 2; Tarakanova et al., 2018). 278, 4855348562. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Chem. Trends Biotechnol. Transl. doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Sci. Trends towards maximal association are apparent when each of these parameters is varied. Biochemistry 8, 28372845. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. Med. CICADA TURNS 20: How synthetic skin biotech Elastagen changed lives Patient Homepage | Accredo Tropoelastins C-terminal domain 36 (yellow) does not fall into either category as it contains a distinct sequence capped with a Gly-Arg-Lys-Arg-Lys (GRKRK) motif and is primarily involved in cell interactions. (2017). Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). 280, 4093940947. 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. (1988). doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Powered by Madgex Job Board Software. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Elastin - an overview | ScienceDirect Topics 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). doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Sci. Biol. Ltd., which was sold to Allergan, now a division of AbbVie. Biochemistry 36, 84138421. Tropoelastins sequence and domain arrangement. 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. The cross-linking domains are enriched for either Lys-Pro (KP) or Lys-Ala (KA) motifs and form cross-links that link growing tropoelastin chains during elastogenesis; note that exon 6 encodes a KA domain. Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. February 14, 2018 Michael Patrini. Front. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Four days after a heart attack, purified tropoelastin was injected into the heart. 37, 698702. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. Chem. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. Communication: coacervation of tropoelastin results in fiber formation. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). EBP plays two roles in the assembly of elastin. This process is reversible and thermodynamically controlled and does not require protein cleavage. (1989). Cell. Allergans success is powered by our global colleagues commitment to being Bold for Life. Pediatr. 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. The N-terminal head caps an extended coil region that consists of domains 218. Advanced BioMatrix - Recombinant Tropoelastin, Lyophilized #5052 J. Pathol. Commun. J. Biomol. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Dermatol. Acta 303, 363369. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Synthesis and structural studies of a pentapeptide sequence of elastin. However, there are aspects of this model that warrant further investigation. J. Biochem. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). FASEB J. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Earnings, adjusted for non-recurring costs, came . Cell Biol. Domains 12 to 16 of tropoelastin promote cell attachment and spreading Tropoelastin: a novel marker for plaque progression and instability. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Biochem. Soluble matrix protein is a potent modulator of mesenchymal stem cell Matrix Biol. 28, 432441. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. J. Biol. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. 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. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. 289, 1005710068. 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). Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. Fibrillin-1 interactions with heparin. All authors contributed to writing and editing the review. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Acta 761, 1722. 276, 3603536042. 396, 870873. 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). Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Biochim. 300, 13351359. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). (2015). 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). The isoform-function theory is further reinforced by the presence of two different ELN genes within teleosts that are differentially expressed both spatially and temporally during development (Miao et al., 2007). Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). J. Ultrastruct. Cell Biol. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). Genet. 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. 260, 32553258. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Elastin - Wikipedia (2013). (1973). 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. 270, 1777817783. Med. Domain 26 of tropoelastin plays a dominant role in association by coacervation. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. . 26, 125135. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. Characterization of an unusual tropoelastin with truncated C-terminus in the frog. FEBS J. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Chem. Elastin synthesis during perinatal lung development in the rat. (2006). 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). 9:eaai7466. 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). (2017). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Nat. Albert, E. N. (1972). A comprehensive map of human elastin cross-linking during elastogenesis. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Matrix Biol. The lysines of domain 15 and 17 are believed to play key roles in this interaction. 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 . Tropoelastin #5052. 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). Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Mol. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. 26, 17001709. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Allergan announced that it would be accessing Elastagen's next generation Juvederm dermal filler injectable portfolio, which will now also boast its "key 'youth protein' tropoelastin". 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. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014). A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. Acta Gen. Subj. "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Am. Anal. Fell muir lecture: collagen fibril formation in vitro and in vivo. Matrix Biol. Tropoelastins domains each arise from single exons of the ELN gene. (2018). Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Natl. 79, 277284. No use, distribution or reproduction is permitted which does not comply with these terms. Implications for microfibril and elastic fiber assembly. 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. Mater. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. FEBS J. Biophys. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). (2018). 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.