The ERC binds elastin derived peptides, which are the product of proteolytic activity of soluble and insoluble elastin by various elastases. 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. Natl. 258, 118. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. Pharm. J. Biol. B., Broekelmann, T. J., et al. Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. 29, 152159. Biol. Proc. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. (2012). Biopolymers 103, 563573. Acad. 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. Furthermore, the SAXS/SANS structure has been mapped to an elastic network model with tunable stiffness to probe the role of tropoelastins flexibility in fiber assembly (Yeo et al., 2016). Elastagens 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. J. Exp. (2007). Form. 266, 308314. doi: 10.7554/eLife.26526. doi: 10.1038/nature06669, Cox, B. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. Targeted modulation of tropoelastin structure and assembly. Elastin synthesis in arterial smooth muscle cell culture. Implications for microfibril and elastic fiber assembly. Hogan Lovells represented Elastagen Pty Ltd. on the deal. Mol. 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. Genet. Proc. doi: 10.1016/j.matbio.2008.02.006, Phinikaridou, A., Lacerda, S., Lavin, B., Andia, M. E., Smith, A., Saha, P., et al. Acad. (2012). Invest. Sci. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. 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). doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. 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. Chem. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). Elastin: molecular description and function. Tropoelastin: a novel marker for plaque progression and instability. Matrix Biol. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). J. Biol. 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). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. Pediatr. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. 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. With leaps in the improvement of cryogenic electron microscopy to characterize flexible molecules, we predict that this approach will contribute to a deeper understanding of tropoelastin structure and self-assembly in the context of endogenous fiber formation and biomaterials fabrication. 3, 4 Elastin has a very low rate of turnover, so it . U.S.A. 115, 73387343. III. Biol. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. Collapse Section. Eur. Coacervation of tropoelastin. doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Partridge, S. M. (1966). The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. 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. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Res. 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. Acad. doi: 10.1002/bip.1981.360200611. Thus, elastin is responsible, in great part, for the properties of elastic fibers. (2019). 58, 270277. 37, 698702. Domain 26 of tropoelastin plays a dominant role in association by coacervation. 28, 379382. N. Y. Acad. (2014). 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). Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Matrix Biol. Chem. (1995). Sci. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. 252, 351365. Cell Biol. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. U.S.A. 84, 56805684. Acad. (2006). 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). 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. 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. 26, 115124. J. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Res. 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). Molecular modeling of protein materials: case study of elastin. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. 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). Four days after a heart attack, purified tropoelastin was injected into the heart. Nature 437, 9991002. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. Foster, J. U.S.A. 110, 28522857. Biol. J. J. Med. 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). Investig. Fibrillin-1 interactions with heparin. Cooperativity between the hydrophobic and cross-linking domains of elastin. J. Therm. Biochem. 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). Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. J. Mol. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Chem. Mol. 280, 3052630537. EBP plays two roles in the assembly of elastin. Ann. Communication: coacervation of tropoelastin results in fiber formation. 284, 22162230. Today Biol. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). A model two-component system for studying the architecture of elastin assembly in vitro. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). Acad. 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. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). 31, 261272. (2015). J. Biol. The compositions include a coalescence-controlling agent in the form of a polysaccharide or polysaccharide derivative, in an amount effective for providing the substance with the properties of flow, enabling injection. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Arch. Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. doi: 10.1021/acs.biomac.6b01759, Mackay, J. P., Muiznieks, L. D., Toonkool, P., and Weiss, A. S. (2005). Dermatol. Biochemistry 45, 95189530. Cellular expression of tropoelastin mRNA splice variants. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). Natl. Synthesis and structural studies of a pentapeptide sequence of elastin. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. 276, 3603536042. Interestingly, the location and orientation of different domains that contacted each other during self-assembly was noted to be heterogeneous, resulting in head-to-head, tail-to-tail, head-to-tail, and lateral interactions (Tarakanova et al., 2019a). doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). This process is reversible and thermodynamically controlled and does not require protein cleavage. Sci. 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). J. Biol. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Fluorescently labelled mesenchymal stem cells growing on tropoelastin. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. In addition to interacting with tropoelastin, fibulin-4 and -5 are capable of also binding LOX and fibrillin-1 and, thus, have key roles in facilitating elastogenesis (Hinderer et al., 2015). 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). By leveraging the advantages of computational models, such as elastic network models, full-atomistic models and coarse grained models, as depicted in Figure 2, the correlation between the structure, motions, and the functionality of tropoelastin have recently been explored in depth (Yeo et al., 2016; Tarakanova et al., 2018, 2019a). 82, 335340. 26, 524540. 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.. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Med. 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. The majority of tropoelastin synthesis occurs during perinatal development (Myers et al., 1983; Noguchi et al., 1990), however, synthesis may be triggered in response to tissue damage (Parks et al., 1992) or during diseases such as atherosclerosis (Phinikaridou et al., 2018). These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). J. Hum. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. eLife 6:e26526. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. (2006). Biochemistry 37, 1461314622. 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 . Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. Baul, U., Bley, M., and Dzubiella, J. Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Tropoelastin massively associates during coacervation to form quantized protein spheres. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. doi: 10.1002/jcp.20546, Kozel, B. (2003). 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. Natl. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). The authors wrote and submitted this manuscript in response to an invitation by the Editor. Am. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . Coarse-grained model of tropoelastin self-assembly into nascent fibrils. Acta Histochem. 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). For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. 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). 9:eaai7466. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Rep. 8, 116. 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. (1988). Sequence and structure determinants for the self-aggregation of recombinant polypeptides modeled after human elastin. J. Biol. The last 17 amino acid residues of the C-terminus of domain 36 are also implicated in HS interactions; the last four residues are Arg-Lys-Arg-Lys and are positively charged at physiological pH which provides a charged cluster capable of binding negatively charged HS (Broekelmann et al., 2005). U.S.A. 116, 20422051. doi: 10.1016/s0934-8832(11)80057-0. Biopolymers [Epub ahead of print]. 280, 4093940947. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Biophys. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Biomaterials 127, 4960. Computational smart polymer design based on elastin protein mutability. 43, 131138. The study is designed to evaluate the efficacy of two formulations of a cross-linked tropoelastin matrix given the product codes ELAPR002f (collectively referred to as ELAPR or ELAPR002) for the treatment of rolling atrophic acne scars when administered as intradermal implants. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Biopolymers 29, 16991706. J. Clin. The alignment of the tropoelastin aggregates . 149, 282289. Int. 41, 494497. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. This deduction has been corroborated by the observation that tropoelastin with multiple allysine modifications displays conformational sampling comparable to that of the wild-type molecule, suggesting it is more likely to readily participate in self-assembly. J. Biol. Matrix Biol. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Res. The N-terminal head caps an extended coil region that consists of domains 218. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. 260, 32553258. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. 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). 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). Pathol. Sci. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Matrix Biol. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. A comprehensive map of human elastin cross-linking during elastogenesis. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. 26, 17001709. Elastin is one of the most abundant proteins in your body. 410, 317323. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. The stiffness that arose due to amino acid substitutions partially determined resultant secondary structure which, in turn, impacted assembly (Prhashanna et al., 2019). Chem. doi: 10.1021/bi034837t, Tamburro, A. M., Guantieri, V., and Gordini, D. D. (1992).
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