Sci. doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). Such models could be used in conjunction with the full molecular model of tropoelastin to examine the self-assembly of discrete regions to understand the impacts of amino acid substitutions in disease. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . Computational smart polymer design based on elastin protein mutability. Genet. Fabricating organized elastin in vascular grafts. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. Tropoelastins sequence and domain arrangement. Amino acid conformational preferences and solvation of polar backbone atoms in peptides and proteins. 126, 283290. doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). Thus, elastin is responsible, in great part, for the properties of elastic fibers. No use, distribution or reproduction is permitted which does not comply with these terms. Molecular dynamics modeling of aggregating tropoelastin-derived peptide chains points to the maintenance of a hydrated, disordered, liquid-like state due to the formation of short-lived inter-chain bonds (Rauscher and Pomes, 2017; Reichheld et al., 2020), mostly likely due to the inducement of random coils by PG repeats (vide supra). Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. J. Biol. Elastogenesis is the term that collectively describes the hierarchical process of elastic fiber formation, and is comprised of distinct phases: tropoelastin synthesis, coacervation, cross-linking, and deposition. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). Powered by Madgex Job Board Software. J. Biol. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. Tropoelastin massively associates during coacervation to form quantized protein spheres. 10, 15321541. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Proc. (2006). Chem. 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). 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. 43, 131138. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Figure 2. 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). Sci. J. Biol. Sci. 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). In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. 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). 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. Mol. Sci. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). U.S.A. 110, 28522857. Trends Biotechnol. 282, 1248412491. Chem. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). Scientists find way to heal scars left behind by heart attacks Structure 14, 16671676. Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. 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). Unsubstituted models are also critical to understanding self-assembly. doi: 10.1074/jbc.270.30.17778, Cain, S. A., Baldock, C., Gallagher, J., Morgan, A., Bax, D. V., Weiss, A. S., 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). 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. doi: 10.1016/j.ajhg.2009.09.013. Biol. 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). doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). J. Biol. (1995). Chem. Natl. J. Pathol. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. 25, 492504. 149, 282289. (2020). The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. Allergan Highlights Key Growth Drivers for Medical Aesthetics - PR Newswire 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Conformational transitions of the cross-linking domains of elastin during self-assembly. 284, 22162230. J. Biol. 85, 593605. [Epub ahead of print]. (2014). Acta Gen. Subj. 280, 4093940947. Ltd., which was sold to Allergan, now a division of AbbVie. Aaron, B., and Gosline, J. Int. 281, 2375723765. (2006). doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. 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). A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. 1862, 324334. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. 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). AW gratefully acknowledges NHMRC funding (Ref: 1195827). Cellular activities are mediated through interactions between tropoelastin or EDPs and specific receptors on the cell surface. (2014). Pathol. Chem. Biophys. Genet. 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. Allergan Highlights Key Growth Drivers for Medical Aesthetics 34, 8190. Acad. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. J. Biol. 2:e1501145. Eng. The N-terminal head caps an extended coil region that consists of domains 2-18. Fed. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). J. Struct. This acquisition and the development of a next generation of injectables based on this technology will ensure Allergan offers innovative filler products for years to come., Robert Daniels, Elastagen CEO, noted: Partnering with Allergan, a leader in medical aesthetics, is incredibly exciting. Micron 41, 268272. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). Sci. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). J. Biochem. Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. 26, 524540. Biochem. A model two-component system for studying the architecture of elastin assembly in vitro. 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. 112, E4408E4415. 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. Acad. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. 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. (2013). J. Mol. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge 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. Biophys. doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). Weiss Lab Home Allergan Snaps Up Sydney Biotech for Upfront Payment of US $95M 275, 2844928454. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. 15, 786801. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Biomacromolecules 20, 11781189. Matrix Biol. Nat. Am. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. doi: 10.1021/bi400760f, Miao, M., Reichheld, S. E., Muiznieks, L. D., Sitarz, E. E., Sharpe, S., and Keeley, F. W. (2017). doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). Eng. Lab. 266, 308314. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). 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. 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. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. Healthcare Investment Banking - The Walden Group Chem. The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). [Epub ahead of print]. Implications for tissue specificity and durability of elastic tissue. 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. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Proc. Chem. 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). doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Fibrillin-1 interactions with heparin. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). Coacervation involves the agglomeration of protein molecules, which is an . A., Gray, W. R., and Franzblau, C. (1973). 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 . Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. doi: 10.1021/bi00835a022, Lockhart-Cairns, M. P., Newandee, H., Thomson, J., Weiss, A. S., Baldock, C., and Tarakanova, A. Natl. Sci. 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). A., Torres, A. R., Alvarez, V. L., and Janata, J. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). (2021). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Biochim. 58, 270277. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). (2017). J. Therm. Proc. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). 26, 125135. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. (2017). Nature 246, 461466. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late However, there are aspects of this model that warrant further investigation. 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. Structure of the elastin gene and alternative splicing of elastin mRNA: implications for human disease. J. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). 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). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. 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). doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). Parameter, Testing, and Method. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Biomaterials 139, 163171. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. Biol. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Due to the lack of a full-atomistic structure, a number of elastin derivatives, including isolated tropoelastin domains (Toonkool et al., 2001; Mackay et al., 2005; Dyksterhuis et al., 2007; Dyksterhuis and Weiss, 2010) and synthetic elastin-derived peptides (EDPs) (Luan et al., 1990; Tamburro et al., 1992; Kentsis and Sosnick, 1998; Kumashiro et al., 2006; Reichheld et al., 2014, 2017; Muiznieks et al., 2015; MacEwan et al., 2017; Tarakanova et al., 2017) have been studied to understand tropoelastins domain level properties. Acad. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Tropoelastin: a novel marker for plaque progression and instability. (2019a). doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. This process is reversible and thermodynamically controlled and does not require protein cleavage. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. (2017). 270, 1777817783. 250, 9298. Crosslinking [ edit] 3, 28322844. (2005). 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. Fluor: Q4 Earnings Snapshot | AP News doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. B., Broekelmann, T. J., et al. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Circ. Tropoelastin - an overview | ScienceDirect Topics doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. 258, 118. Production of recombinant human tropoelastin: Characterization and Novel Recombinant Tropoelastin Implants Restore Skin Extracellular Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. 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. Bioeng. Water structure and elastin-like peptide aggregation. Biol. 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. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right. Biosynthesis and nature of elastin structures. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Biochim. J. Clin. This review focuses on recent developments that have shaped our current knowledge of elastin assembly through understanding the relationship between tropoelastins structure and function. Chem. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. 589(19 Pt A), 24772486. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. Biomacromolecules 18, 599609. Additionally, coarse-graining the full-atomistic model has allowed for the examination of mesoscale tropoelastin assembly and, in particular, deciphered the orientation of tropoelastin molecules that occurs during early stage assembly (inset image) (Tarakanova et al., 2019a). Elastagen's technology is based on human tropoelastin . Cell. Tropoelastin: a versatile, bioactive assembly module - PubMed HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Natl. 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. 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). Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. J. Biol. Am. J. Biol. Tropoelastin is a unique protein with biochemical and physical properties that allow it to rapidly self-assemble into fibrous structures. Coacervation characteristics of recombinant human tropoelastin. 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. 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 . 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. Partridge, S. M. (1966). Acad. U.S.A. 115, 73387343.