J. Biol. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). 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). Sci. 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. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). The alignment of the tropoelastin aggregates . J. Biol. Patient Homepage | Accredo U.S.A. 109, 28782883. (2019). The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Biol. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. Novel Recombinant Tropoelastin Implants Restore Skin Extracellular Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). (2015). 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). Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Tropoelastin Improves Post-Infarct Cardiac Function No use, distribution or reproduction is permitted which does not comply with these terms. Biopolymers [Epub ahead of print]. B., Broekelmann, T. J., et al. U.S.A. 108, 43224327. Coacervation characteristics of recombinant human tropoelastin. doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Natl. Sci. Tropoelastin has a defined shape in solution but paradoxically also displays a large percentage of flexible, disordered regions needed for molecular elasticity (4, 5).The tertiary structure of human tropoelastin represents an ensemble of elastic conformers (3, 6), yet occasional conserved sequence elements hint at requirements for functional demands in one or more key parts of this molecule (7 . Direct observation of structure and dynamics during phase separation of an elastomeric protein. Elastin-like polypeptides as models of intrinsically disordered proteins. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Production of recombinant human tropoelastin: Characterization and Elastin: Structure, Function, Skin Care & Supplements - Cleveland Clinic Elastagens tropoelastin is identical to that present in human tissue, and has many potential clinical applications, including treatment for acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Hogan Lovells represented Elastagen Pty Ltd. on the deal. However, there are aspects of this model that warrant further investigation. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). Front. Mol. Elastogenesis in human aorta: an electron microscopic study. Visconti, R. P., Barth, J. L., Keeley, F. W., and Little, C. D. (2003). Chem. Acad. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. 26, 524540. (2019a). Tropoelastin is typically used as a thin coating on tissue culture surfaces. (2012). The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. 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). 98, 416. Dermatol. Biomacromolecules 20, 11781189. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. J. Biol. 286, 35943610. Allergan acquired Elastagen primarily for the injectable product portfolio (acne scars/stretch marks aesthetics). doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., et al. 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 126, 563574. Matrix Biol. 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). The hydrophobic domains vary in length, with the majority of the shorter (95 residues) domains occurring near the N-terminus, while the longer (up to 55 residues) domains are found within tropoelastins central and C-terminal regions (Indik et al., 1989). doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). (2011). into 200 nm then 12 m spherules, which eventually grow and stabilize into spherules 26 m in diameter (Clarke et al., 2006; Kozel et al., 2006; Tu and Weiss, 2010; Tu et al., 2010). FEBS Lett. 280, 3052630537. [Epub ahead of print]. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. Sequence and structure determinants for the self-aggregation of recombinant polypeptides modeled after human elastin. Allergan Highlights Key Growth Drivers for Medical Aesthetics - PR Newswire Biol. More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). Exp. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. This suggests the ERCs primary signal pathways are involved in wound recognition through fragments of elastin, where EDPs are formed as a result of elastic tissue damage. Transl. 26, 115124. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. . Targeted modulation of tropoelastin structure and assembly. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. J. Struct. 82, 335340. Parameter, Testing, and Method. 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). The ELN gene provides instructions for making a protein called tropoelastin. 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). Mater. 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). doi: 10.1038/nature04085. 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). Co-author Professor Anthony Weiss from the Charles Perkins Centre and Faculty of Science explained: "Tropoelastin can repair the heart because it is a precise replica of the body's natural elastic protein,". 27, 441450. 9:eaai7466. Acad. Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Biosynthesis and nature of elastin structures. Biochemistry 42, 1334713362. 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). A comprehensive map of human elastin cross-linking during elastogenesis. Chem. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). 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. J. Pathol. Cell Res. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. 270, 1777817783. II. Genet. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. 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 . Elastin is extensively cross-linked and difficult to break apart into monomers even under harsh conditions, thus, initial strategies included feeding animals a copper deficient diet to prevent lysyl oxidase (LOX) cross-linking of tropoelastin; however, this proved inefficient and time consuming (Wise and Weiss, 2009; Tarakanova et al., 2018). It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Matrix Biol. (1983). Albert, E. N. (1972). J. Hum. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). Trends Biotechnol. doi: 10.1021/acs.biomac.0c00546, Bochicchio, B., Floquet, N., Pepe, A., Alix, A. J., and Tamburro, A. M. (2004). doi: 10.1016/j.biomaterials.2017.04.050, Keywords: elastin, elastic fibers, tropoelastin, computational modeling, assembly, Citation: Ozsvar J, Yang C, Cain SA, Baldock C, Tarakanova A and Weiss AS (2021) Tropoelastin and Elastin Assembly. Further to this, the flexibility of the hydrophobic domains may also play a key role in self-assembly. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas Biochem. 13, 739743. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. Elastin, arterial mechanics, and cardiovascular disease Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. This content is for members only. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). 266, 308314. Although there is no 3D structure for porcine tropoelastin, porcine tropoelastin differs from that of humans (Sandberg et al., 1977), leaving it unclear as to whether these domains align as expected in human tissue. 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). All authors contributed to writing and editing the review. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. Eur. Med. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. 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). Arch. Collapse Section. Acta 303, 363369. 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). 281, 2375723765. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). 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). Powered by Madgex Job Board Software. (2017). doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Matrix Biol. 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. Elastin is one of the most abundant proteins in your body. Biochemistry 8, 28332837. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. Characterization of the complete human elastin gene. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). To get started with texting, you will need: Your phone number J. Biochem. Synthesis and structural studies of a pentapeptide sequence of elastin. 278, 4855348562. Genet. doi: 10.1038/nature06669, Cox, B. doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). U.S.A. 84, 56805684. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. 276, 4457544580. The authors wrote and submitted this manuscript in response to an invitation by the Editor. Tropoelastin massively associates during coacervation to form quantized protein spheres. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. 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). 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). 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).
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