tropoelastin allergan

doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). It is likely that, as a general rule, integrin binding to tropoelastin is mediated via GAGs, which is facilitated by the repetition of tropoelastins primary sequence and the surface exposure of positively charged similar domains (Lee et al., 2017; Bochicchio et al., 2021). 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 (). 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,". Interactions with these integrins on the surface of mesenchymal stem cells, either through surface bound or as soluble tropoelastin, promote MSC proliferation and phenotypic maintenance via FAK and PKB/AKT (Yeo and Weiss, 2019). Implications for tissue specificity and durability of elastic tissue. doi: 10.1016/s0934-8832(11)80057-0. A model two-component system for studying the architecture of elastin assembly in vitro. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). 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). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). (2012). Coacervation optimally occurs at physiological temperature, however, in vitro coacervation can also occur at lower temperatures depending on experimental conditions and the choice of tropoelastin isoform or derivative (Yeo et al., 2011). Bioeng. Fibrillin-1 interactions with heparin. Biomaterials 139, 163171. Cell Biol. Cooperativity between the hydrophobic and cross-linking domains of elastin. Elastin is a critical skin protein consisting of crosslinked tropoelastin. 220, 312324. Matrix Biol. Adv. Sci. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Remodelling the extracellular matrix in development and disease. doi: 10.1016/0005-2795(73)90368-1, Franzblau, C., Faris, B., and Papaioannou, R. (1969). 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. Cell Res. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. Possible role in nucleated assembly. Chem. 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. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. Eng. (2011). doi: 10.1002/jcp.20546, Kozel, B. Natl. Figure 1. Engineering a highly elastic human protein-based sealant for surgical applications. (2020). PLoS One 7:e46130. Arch. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). Cell Biol. (1983). Proc. 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. Biol. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. Allergan announced that it would be accessing Elastagen's next generation Juvederm dermal filler injectable portfolio, which will now also boast its "key 'youth protein' tropoelastin". 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). Arch. Detailed Description: Molecular model for elastin structure and function. Unsubstituted models are also critical to understanding self-assembly. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. J. Biol. 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. 37, 698702. The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). 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). Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. 4, 508524. Parameter, Testing, and Method. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. Acta 761, 1722. Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. doi: 10.1111/febs.14114, Lent, R. W., Smith, B., Salcedo, L. L., Faris, B., and Franzblau, C. (1969). (2007). doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. Gene 154, 159166. 28, 379382. Cell Biol. 120, 419426. The most crucial of these properties is the ability to undergo many stretch-recoil cycles whilst maintaining the structural and functional integrity of elastic tissues over an organisms lifetime. Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. 280, 3052630537. 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 . Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Biol. 3, 4 Elastin has a very low rate of turnover, so it . 270, 1777817783. 264, 88878891. Matrix Biol. Tropoelastin is the soluble precursor of elastin that is secreted as a 60-70-kDa monomer by elastogenic cells such as fibroblasts, lung alveolar cells, chondrocytes, and vascular SMCs [16]. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Cryo-electron microscopy is a rapidly developing method and likely to contribute to structural knowledge of tropoelastin. (2018). Matrix Biol. Bull. Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. 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. Tropoelastin is secreted as a 6070 kDa protein to the cell surface where it participates in self-assembly (Hinek and Rabinovitch, 1994; Figure 3). 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). Moreover, fibulins are essential for elastic fiber directionality, as fibroblasts with fibulin-4 and -5 knockdowns generate poorly formed elastic fibers (Yamauchi et al., 2010), and fibulin-4 / mice display aberrant, poorly cross-linked, and non-fibrous elastin (McLaughlin et al., 2006). Biochemistry 45, 99899996. 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 . Sci. J. Med. 266, 308314. Mater. Cell Physiol. We are making enrolling in text alerts easier than ever. J. Biol. U.S.A. 115, 73387343. Tropoelastins amino acid sequence predominantly consists of non-polar residues including glycine, valine, alanine, and proline (Debelle and Tamburro, 1999). doi: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Sequence variants of human tropoelastin affecting assembly, structural characteristics and functional properties of polymeric elastin in health and disease. Synthesis and structural studies of a pentapeptide sequence of elastin. Chem. 26, 115124. Pediatr. J. Biol. Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. ACS Biomater. Protein Eng. 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). Invest. 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. Coacervation characteristics of recombinant human tropoelastin. J. Biochem. The smooth muscle cell. Mol. Molecular model of human tropoelastin and implications of associated mutations. Biochim. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. Proc. 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). Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. (2021). Int. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. Molecular docking studies utilizing tropoelastin and the 3D structure of LOX1 (Vallet et al., 2018) may assist in our understanding as to whether the enzyme has a preference for modifying particular tropoelastin residues. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. (2005). 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). (1995). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Proc. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). (1989). 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). Today Biol. 85, 593605. Med. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late N. Y. Acad. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . 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). Matrix Biol. Crosslinking [ edit] 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). Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . (2014). Tropoelastin spherules assemble at the cell surface before deposition onto the microfibrillar scaffold in cell culture systems at physiological temperature (Kozel et al., 2006). 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. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. Molecular modeling of protein materials: case study of elastin. Elastin synthesis in arterial smooth muscle cell culture. 68, 411419. Coarse-grained model of tropoelastin self-assembly into nascent fibrils. 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. 276, 3603536042. J. Biochem. Exp. . 149, 282289. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. Matrix Biol. Poly (Val-Gly-Gly-Leu-Gly). Rep. 8, 116. doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). doi: 10.1074/jbc.M308465200, Miao, M., Bruce, A. E., Bhanji, T., Davis, E. C., and Keeley, F. W. (2007). J. Hum. 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). 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. 13, 739743. J. Struct. (1988). 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. Trends Biotechnol. 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). For more information, visit Elastagens website atwww.elastagen.com. Approximately 90% of tropoelastins lysines undergo modification and/or participate in cross-links, indicating that mature elastin is extensively cross-linked (Kozel et al., 2003; Schmelzer et al., 2019). J. Exp. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. (1989). (2017). (2019). Sci. Mater. 150, 154162. Elastin is one of the most abundant proteins in your body. This content is for members only. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). 38, 280291. These ordered structures can include -helices and -structures (Vrhovski et al., 1997), which depend on the amino acid content and arrangement of domains (He et al., 2012; Reichheld et al., 2014, 2017; Muiznieks et al., 2015) and the choice of solvent (Reiersen and Rees, 2000; Muiznieks et al., 2015). Res. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. Cell Biol. 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). Even after being able to produce recombinant tropoelastin at scales suited to characterization studies, traditional techniques have not yet produced an experimentally verified atomistic structure (Martin et al., 1995; Tarakanova and Buehler, 2013). Biol. Sci. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). 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. (2008). 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). On a per-share basis, the Irving, Texas-based company said it had profit of 1 cent. Nat. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. J. Biol. Proc. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. (2017). Acta 303, 363369. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). 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). 43, 131138. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. J. Biol. Eng. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Figure 3. (2001). A comprehensive map of human elastin cross-linking during elastogenesis. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. Acad. Biochemistry 52, 77317741. 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. Allergan is an industry leader in Open Science,a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Its estimated half-life of 70 years (Shapiro et al., 1991) is due to its extensive cross-linking and high hydrophobicity, which render it resistant to degradation (Vrhovski and Weiss, 1998; Schrader et al., 2018; Hedtke et al., 2019). Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. Baul, U., Bley, M., and Dzubiella, J. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. Reichheld, S. E., Muiznieks, L. D., Huynh, Q., Wang, N., Ing, C., Miao, M., et al. 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. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). Thus, computational approaches can be considered as important means to complement wet bench experiments. Conformational transitions of the cross-linking domains of elastin during self-assembly. 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 . Biochemistry 42, 1334713362. Dermatol. Differential expression of two tropoelastin genes in zebrafish. Sci. Invest. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. J. Foster, J. Biophys. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. Biochim. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). 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). 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. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. 278, 4855348562. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. 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. 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. Commun. February 14, 2018 Michael Patrini. Biophys. Matrix Biol. 98, 416. 82, 335340. Pathol. 10, 441454. These remarkable properties arise from its sequence and structure, which render tropoelastin structurally highly flexible but not disordered (Tarakanova et al., 2018). Isolation and characterization of crosslinked peptides from elastin. Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. Trends Biotechnol. Sci. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. 27, 441450. 33, 54685481. Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). No use, distribution or reproduction is permitted which does not comply with these terms. Chemistry 10, 31663176. Recycling of the 67-kDa elastin binding protein in arterial myocytes is imperative for secretion of tropoelastin. 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). 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: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. J. Biomol. 25, 10231029. 15, 786801. Lab. (1965). (2019a). Biochemistry 8, 28372845. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. doi: 10.1016/j.matbio.2006.10.002, Dyksterhuis, L. B., and Weiss, A. S. (2010). Biol. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. The smallest amino acid, glycine is known to promote flexibility within local structures due to lack of steric hindrance, whereas prolines restrictive sidechain inhibits conformational sampling and disrupts the formation of prolonged secondary structures (Roberts et al., 2015). [Epub ahead of print]. doi: 10.1016/j.biochi.2004.03.002, Sandberg, L. B., Gray, W. R., Foster, J. Tropoelastin: a versatile, bioactive assembly module. doi: 10.1074/jbc.M609505200, Dyksterhuis, L. B., Baldock, C., Lammie, D., Wess, T. J., and Weiss, A. S. (2007). doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). Aaron, B., and Gosline, J. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). Targeted modulation of tropoelastin structure and assembly. 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). doi: 10.1016/s0021-9258(19)83613-x, Miao, M., Bellingham, C. M., Stahl, R. J., Sitarz, E. E., Lane, C. J., and Keeley, F. W. (2003). doi: 10.1002/ajmg.1320340115, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Sheppard, P., Anderson, N., Rosenbloom, J. C., et al. (1995). 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). Tropoelastins primary sequence is low in complexity and contains repetitive motifs. 589(19 Pt A), 24772486. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. 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. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). 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. 275, 2844928454. doi: 10.1016/s0968-4328(99)00082-7, Tajima, S., Wachi, H., Uemura, Y., and Okamoto, K. (1997). All rights reserved. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. 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). The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. doi: 10.1074/jbc.M510833200, Lee, P., Bax, D. V., Bilek, M. M., and Weiss, A. S. (2014).

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