doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Elastin and other dermal components are gradually lost through aging, sun damage, and following injury, highlighting a need to replace these components to repair the skin. Tropoelastin is typically used as a thin coating on tissue culture surfaces. 149, 282289. Biophys. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). 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. 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). Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. 26, 17001709. 33, 54685481. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Possible role in nucleated assembly. Synthesis and structural studies of a pentapeptide sequence of elastin. Dermatol. 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). This model revealed that tropoelastin maintains a canonical or average structure based on the distribution of its possible conformations in spite of its flexible nature (Figure 2), as well as the possible roles that local structures play in biological processes, specifically, elastogenesis (Tarakanova et al., 2019b). Lysinonorleucine. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). Pathol. Adv. U.S.A. 112, E4408E4415. Biochem. Exp. A single tropoelastin molecule can stretch up to eight times its resting length and has a Youngs modulus (tensile stiffness) of 3 kPa (Baldock et al., 2011) in comparison to elastins extensibility of 150% and stiffness of 1 mPa (Aaron and Gosline, 1981). 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). Elastic fibers provide tissues with mechanical resilience, durability, and cell interactivity, which support a diverse range of specialized functionality. Natl. Trends Biotechnol. doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Elastagen Pty Ltd, 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 plc, a leading global biopharmaceutical company, has agreed to acquire Elastagen. 289, 1005710068. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). (1983). Acad. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 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. Matrix Biol. Cell Biol. Lab. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. (2005). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Acta Biomater. 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. Matrix Biol. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. 207, 8796. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Biotechnol. 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 . doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). Unlike hydrophobic domains, cross-linking domains in isolation are unable to self-assemble; thus, they have been studied in the context of the cross-linking of elastin-derived biomaterials (Annabi et al., 2017; Yue et al., 2017). Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. 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. Tropoelastins sequence and domain arrangement. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. The elasticity of organs and tissues in vertebrates is due to the presence of elastin, and an insoluble protein whose soluble monomer, tropoelastin, is enzymatically cross-linked through -amino groups of lysine residues. Acta 303, 363369. 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. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Natl. Sci. Elastagen's technology is based on human tropoelastin . doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. 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). Tropoelastin: a novel marker for plaque progression and instability. 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. Aaron, B., and Gosline, J. 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). 281, 2375723765. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). (2016). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late 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. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Fluor: Q4 Earnings Snapshot. Biol. Fed. 2:e1501145. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. 289, 14671477. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. 85, 593605. 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. 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. J. Biol. For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Structure 14, 16671676. Biomed. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Biochemistry 37, 1461314622. IRVING, Texas (AP) IRVING, Texas (AP) Fluor Corp. (FLR) on Tuesday reported fourth-quarter net income of $9 million, after reporting a loss in the same period a year earlier. The authors wrote and submitted this manuscript in response to an invitation by the Editor. 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). Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. (2012). 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. Thus, elastin is responsible, in great part, for the properties of elastic fibers. Stages of hierarchical assembly of elastic fibers. Biochemistry 45, 99899996. For many years it was difficult to study tropoelastin at an atomic scale, but the application of computational methods, such as full-atomistic molecular dynamics and elastic network models, in combination with powerful low-resolution structural studies, have expanded the field and delivered an enhanced understanding of the mechanisms that contribute to self-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. 260, 32553258. Primary structure of porcine tropoelastin. Chem. 98, 416. 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Water structure and elastin-like peptide aggregation. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). 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). J. Pathol. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Tropoelastins flexibility does not allow it to pack into a crystal lattice and its size renders it too complex to assign atomic interactions using nuclear magnetic resonance (NMR) on a global level (Tamburro et al., 2003, 2006; Bochicchio et al., 2004; Pepe et al., 2008). Chem. doi: 10.1002/bip.1981.360200611. Cell Res. Figure 2. 29, 152159. 220, 312324. Biol. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Biomaterials 127, 4960. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. 84, 6880. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). 27, 441450. 280, 4093940947. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . Proc. 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). Circ. 31, 261272. Allergan's Acquisition of Elastagen. Partridge, S. M. (1966). 58, 270277. Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. Exp. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Deficient coacervation of two forms of human tropoelastin associated with supravalvular aortic stenosis. The presence of tropoelastin spherules fusing to fibrils has been noted in native tissue, demonstrating marked similarities between in vitro and in vivo coacervation (Haust et al., 1965; Albert, 1972; Kozel et al., 2006). 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). FEBS J. Furthermore, tropoelastins hydrophobic and cross-linking domains are arranged in alternating patterns throughout the majority of the molecule, giving rise to both inter- and intra-domain level repetition. Biochemistry 45, 95189530. Elastin is heterogeneously cross-linked. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. (2015). 26, 125135. Banded fibers in tropoelastin coacervates at physiological temperatures. Cell Physiol. 293, 1510715119. Nat. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. 4, 508524. Am. Closer to the base of the molecule, the flexible hinge region between domains 21 and 23 presented with a scissors-like bending, which is now believed to contribute to elasticity and multimeric assembly through enhanced conformational space sampling (Tarakanova et al., 2019b). The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. Proc. Dyn. 26, 524540. However, there are aspects of this model that warrant further investigation. 43, 131138. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). Chem. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Adv. Dermatol. 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 massively associates during coacervation to form quantized protein spheres. Front. Model. (2014). U.S.A. 84, 56805684. (2014). doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Struct. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Allergans success is powered by our global colleagues commitment to being Bold for Life. (2008). (2007). Biol. Identification of an elastin cross-linking domain that joins three peptide chains. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. 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. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. 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). 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. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Bioeng. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. 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). Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. FEBS J. Eur. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment.
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