Mater. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Elastin is a critical skin protein consisting of crosslinked tropoelastin. (1989). Acta Gen. Subj. (2007). A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. Biopolymers 107:e23007. Tropoelastin bridge region positions the cell-interactive C terminus and contributes to elastic fiber assembly. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. 289, 489492. (2019). Coacervation of tropoelastin. 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. 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). doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). 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. 31, 261272. 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. Med. (2015). doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Biochem. Dyn. (2019). Invest. [Epub ahead of print]. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). Communication: coacervation of tropoelastin results in fiber formation. (2006). Computational smart polymer design based on elastin protein mutability. Tropoelastin. (2005). 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). Biol. 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. J. Mol. Biopolymers 20, 12471260. Chem. This temperature is also known as the transition temperature. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). Synthesis and structural studies of a pentapeptide sequence of elastin. 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). 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. J. Biochem. 37, 698702. Chem. Unsubstituted models are also critical to understanding self-assembly. J. Struct. For example, models involving single point mutations at negatively charged residues demonstrated both regional and global destabilization of tropoelastins structure, which were validated by SAXS structures (Yeo et al., 2012; Tarakanova et al., 2018). Exp. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. doi: 10.1016/j.matbio.2006.08.258, Clarke, A. W., Arnspang, E. C., Mithieux, S. M., Korkmaz, E., Braet, F., and Weiss, A. S. (2006). Targeted modulation of tropoelastin structure and assembly. Natl. 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). doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. Adv. Tropoelastin: a novel marker for plaque progression and instability. Matrix Biol. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. 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. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Front. B., Broekelmann, T. J., et al. (2019a). Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Am. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. However, there are aspects of this model that warrant further investigation. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. 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. Acad. 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). (2016). Non-polar residues are a major contributor to protein folding, as their unfavorable interactions with water drive them to bury into the protein core, however, as tropoelastin is comprised of numerous hydrophobic domains, it has been demonstrated that many of these domains will be at least partially solvent exposed (Dyksterhuis et al., 2007). doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Chem. Our Juvederm collection of fillers has sales of over $1 billion globally and is one of the fastest growing parts of our Aesthetics business, said Bill Meury, Chief Commercial Officer at Allergan. Figure 3. It has recently been suggested that fibrillins are capable of stabilizing tropoelastin, possibly for the purpose of selecting conformations that are favorable for elastin assembly (Lockhart-Cairns et al., 2020). Total synthesis and expression in Escherichia coli of a gene encoding human tropoelastin. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. FEBS J. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Biochemistry 8, 28372845. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). J. Biol. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. . Chem. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). 278, 1849118498. Proc. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. doi: 10.1002/jcp.20546, Kozel, B. doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). 84, 6880. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). 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. 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. 34, 8190. 266, 308314. 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 (). Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. 26, 125135. Combinations of these two amino acids result in domains that undergo rapid conformational sampling (Rauscher and Pomes, 2017), which, if perturbed toward a conformation that gravitate toward stability, will assemble into highly ordered amyloid-like fibrils that are not elastomeric (Rauscher et al., 2006; Roberts et al., 2015). (2006). Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. Biotechnol., 25 February 2021, View all
doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). (2012). Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Pepe, A., Flamia, R., Guerra, D., Quaglino, D., Bochicchio, B., Pasquali Ronchetti, I., et al. (2013). The narrow specificity to v3 and 53 may also be beneficial compared with other ECM adhesion molecules such as fibronectin (which can adhere to up to 20 types of integrin) which may compete with and modulate binding to tropoelastin, and deliver opposing effects on cell proliferation. Elastin synthesis in arterial smooth muscle cell culture. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . 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). Primary structure of porcine tropoelastin. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. A new amino acid from hydrolysates of elastin. 150, 154162. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992). J. Biol. J. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). 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. AW is the Scientific Founder of Elastagen Pty. Rev. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Imaging 11:e007303. Tropoelastin massively associates during coacervation to form quantized protein spheres. To get started with texting, you will need: Your phone number Mater. 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). 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). The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. 4, 508524. (2011). 264, 88878891. Parameter, Testing, and Method. The full-atomistic model of tropoelastin was developed based on replica exchange molecular dynamics (REMD) simulations, an accelerated sampling method for molecular dynamics (Tarakanova et al., 2018). Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). 16,17 We have previously shown that monomeric TE is utilized as a substrate by dermal fibroblasts in the formation of elastin fibroblasts in vitro, where doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). 13, 739743. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). 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 . Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. 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). Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Figure 2. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Developing elastic tissue. 281, 2375723765. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Biophys. 220, 312324. A., Ishibashi, H., Werneck, C. C., Keeley, F. W., Zhang, L., et al. Cellular expression of tropoelastin mRNA splice variants. 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. J. J. Ultrastruct. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. Matrix Biol. Differential expression of two tropoelastin genes in zebrafish. Biochimie 86, 173178. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin. PLoS One 7:e46130. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. 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. Figure 1. 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. J. Biol. Biol. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. 28, 432441. 58, 270277. 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. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. (2015). The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Baul, U., Bley, M., and Dzubiella, J. (1988). Matrix Biol. Biosynthesis and nature of elastin structures. 167, 94103. 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). Eur. Tropoelastin #5052. 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). 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). Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. FASEB J. Biochemistry 37, 1461314622. (1983). Biol. (2021). Provides infrastructure for further development and following approval to commercialize Elastagens products, SYDNEY February 7th: Elastagen Pty Limited, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced that it has entered into a definitive agreement under which Allergan, a leading global biopharmaceutical company, has agreed to acquire Elastagen for an upfront payment of US$95M plus contingent, commercial payments.. Domain 36 of tropoelastin in elastic fiber formation. Acta 303, 363369. 250, 9298. (2014). Matrix Biol. Implications for microfibril and elastic fiber assembly. 26, 17001709. Sci. 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). Biol. 126, 563574. Fell muir lecture: collagen fibril formation in vitro and in vivo. Biomacromolecules 20, 11781189. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). 293, 1510715119. Biol. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. 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 bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Struct. Bioeng. Acad. Sci. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. KP domains are found closer toward the N-terminus, whereas KA domains are closer to the C-terminus and include alanine tracts (Indik et al., 1987). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. *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. Trends Biotechnol. 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, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Chem. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Chem. (2012). doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007).