Domains 17-27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. Anal. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. A new amino acid from hydrolysates of elastin. Eng. 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. doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Pharm. 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). 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). 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. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Fluor: Q4 Earnings Snapshot. Tropoelastins sequence and domain arrangement. Fell muir lecture: collagen fibril formation in vitro and in vivo. U.S.A. 116, 20422051. Biochemistry of tropoelastin. (2017). Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Elastins subunit, tropoelastin, is a soluble 6070 kDa protein which has been intensely studied over the past three decades. 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. J. Clin. Chem. 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). 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). 220, 312324. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. Biophys. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Biol. (2020). 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. Biol. Chem. Partridge, S. M. (1966). Biophys. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). A model two-component system for studying the architecture of elastin assembly in vitro. U.S.A. 110, 28522857. 281, 2375723765. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Chem. (2015). 98, 416. (2017). 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. Biochemistry 42, 1334713362. (2014). Structural changes and facilitated association of tropoelastin. (2012). Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. 289, 1005710068. (2015). Cell Biol. 19:e1800250. 27, 441450. Banded fibers in tropoelastin coacervates at physiological temperatures. 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. 69, 89102. Biomed. Tropoelastin is encoded by the ELN gene, which is present in all vertebrates except jawless fish (Chung et al., 2006). Chem. Cytochem. Synthesis and properties of crosslinked recombinant pro-resilin. Biochemistry 52, 77317741. Calorim. 43, 131138. Circ. Natl. Pathol. A., Torres, A. R., Alvarez, V. L., and Janata, J. Biopolymers 20, 12471260. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). 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. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. More recently, it has been demonstrated that KA domains consist of random coil content prior to self-assembly and become more ordered as molecules aggregate, marrying the observations discussed above into a cohesive model within the context of assembly and the requirements of higher-order structures (Reichheld et al., 2014). J. Exp. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. J. Mol. 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. Chem. (2006). Int. Front. Pediatr. It's a stretchy protein that resembles a rubber band it can stretch out (extend) and shrink back (recoil). Four days after a heart attack, purified tropoelastin was injected into the heart. (2005). The liquid structure of elastin. FEBS J. Powered by Madgex Job Board Software. Biol. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. 25, 492504. 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). Biotechnol., 25 February 2021, View all Direct observation of structure and dynamics during phase separation of an elastomeric protein. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. No use, distribution or reproduction is permitted which does not comply with these terms. 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). (2021). (2019). 589(19 Pt A), 24772486. Biophys. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. 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. Mol. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. This content is for members only. J. Chem. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. 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. 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). Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. 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). Biochem. Acta Gen. Subj. Elastin-like polypeptides as models of intrinsically disordered proteins. 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). Figure 2. Importantly, the presence of fibrils indicates that the nanostructures formed during initial assembly contribute to the supramolecular structures that arise during both early (spherule) and later (fibril) stages of elastogenesis. Model. This temperature is also known as the transition temperature. Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). 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). 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 . (1965). Arch. (1977). Biol. Parameter, Testing, and Method. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Mater. Characterization of the complete human elastin gene. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). Matrix Biol. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. 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. doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). 26, 17001709. This process is reversible and thermodynamically controlled and does not require protein cleavage. Form. doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). doi: 10.1074/jbc.M212715200, Kumashiro, K. K., Ho, J. P., Niemczura, W. P., and Keeley, F. W. (2006). Tropoelastin is typically used as a thin coating on tissue culture surfaces. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Biol. 82, 335340. Computational smart polymer design based on elastin protein mutability. Biosynthesis and nature of elastin structures. A comprehensive map of human elastin cross-linking during elastogenesis. 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. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. Tropoelastin #5052. Acad. 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. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 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. 31, 261272. doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). Biophys. (2003). The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. 26, 115124. February 14, 2018 Michael Patrini. Fibrillin-1 interactions with heparin. (2009). 150, 154162. Am. doi: 10.1111/febs.14929, Hinderer, S., Shena, N., Ringuette, L. J., Hansmann, J., Reinhardt, D. P., Brucker, S. Y., et al. Aaron, B., and Gosline, J. 278, 1849118498. 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. Sci. Matrix Biol. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). 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. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. doi: 10.1074/jbc.M113.518381, Lee, P., Yeo, G. C., and Weiss, A. S. (2017). J. Ultrastruct. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. (1995). The coacervate is made insoluble by irreversible crosslinking. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Microfibrils comprise multiple proteins, of which fibrillin-1 is the most common. J. Biol. Int. Exp. Remodelling the extracellular matrix in development and disease. Cryo-electron microscopy for structural analysis of dynamic biological macromolecules. U.S.A. 108, 43224327. Matrix Biol. Thus, computational approaches can be considered as important means to complement wet bench experiments. doi: 10.1016/s0934-8832(11)80057-0. (1983). 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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