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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). 87, 18281834. 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. 29, 152159. (1987). 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. 281, 2375723765. Biochim. Differential expression of two tropoelastin genes in zebrafish. Tropoelastin: a versatile, bioactive assembly module. doi: 10.1002/bip.360291403, Luo, P., and Baldwin, R. L. (1997). Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. 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. doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Biol. 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Biomacromolecules 18, 599609. 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 . Proc. The next stage of elastin assembly involves the deposition of tropoelastin spherules onto the microfibril scaffold of elastic fibers. J. Biochem. 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. The lysines of domain 15 and 17 are believed to play key roles in this interaction. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). Biol. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. J. Biol. FEBS J. 34, 8190. EBP plays two roles in the assembly of elastin. This content is for members only. Genet. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). The process of tropoelastin aggregation is initially reversible, as spherules dissipate if the temperature is lowered (Clarke et al., 2006), however, maintenance of a physiological temperature results in maturation, which is indicated by spherule coalescence and the irreversible formation of fibrillar structures (Cox et al., 1974; Bressan et al., 1983; Mithieux et al., 2005). doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). Lysinonorleucine. Mater. Matrix Biol. Stages of hierarchical assembly of elastic fibers. Comparative genomics of elastin: sequence analysis of a highly repetitive protein. 280, 4093940947. Proc. 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). doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. (1983). Matrix Biol. J. Biol. Biopolymers 107:e23007. doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Am. Cell Biol. U.S.A. 110, 28522857. Tropoelastin #5052. Tropoelastin is typically used as a thin coating on tissue culture surfaces. Int. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). 10, 441454. doi: 10.1073/pnas.1215779110, Noguchi, A., Firsching, K., Kursar, J. D., and Reddy, R. (1990). AW gratefully acknowledges NHMRC funding (Ref: 1195827). Acta Histochem. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. Chem. doi: 10.1074/jbc.RA118.004322, Shapiro, S., Endicott, S., Province, M., Pierce, J., and Campbell, E. (1991). (2003). Trends towards maximal association are apparent when each of these parameters is varied. doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). doi: 10.1074/jbc.M107920200, Tu, Y., and Weiss, A. S. (2010). The narrow specificity to v3 and 53 may also be beneficial compared with other ECM adhesion molecules such as fibronectin (which can adhere to up to 20 types of integrin) which may compete with and modulate binding to tropoelastin, and deliver opposing effects on cell proliferation. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). 289, 1005710068. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. Chem. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. (2014). Pathol. Today Biol. More surprisingly, tropoelastins cross-linking domains are also capable of similar transitions between ordered and disordered structures. Biochimie 86, 173178. Cardiovasc. Integrins canonically bind proteins containing Arg-Glu-Asp motifs, but this sequence is not found in tropoelastin (Lee et al., 2014). Elastagen was one of the inaugural recipients of MDF funding in 2013 and will be the first to successfully repay the funding amount. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). A series of mapping studies have been recently conducted to pinpoint the locations of these cross-links (Schrader et al., 2018; Hedtke et al., 2019; Schmelzer et al., 2019) as their placements are crucial to understanding the resultant molecular orientation of tropoelastin within cross-linked elastin. doi: 10.1074/jbc.M507309200, Brown-Augsburger, P., Tisdale, C., Broekelmann, T., Sloan, C., and Mecham, R. P. (1995). Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. Biophys. Arch. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Self-healing and thermoreversible rubber from supramolecular assembly. With leaps in the improvement of cryogenic electron microscopy to characterize flexible molecules, we predict that this approach will contribute to a deeper understanding of tropoelastin structure and self-assembly in the context of endogenous fiber formation and biomaterials fabrication. Remodelling the extracellular matrix in development and disease. 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). Med. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. 19:e1800250. Natl. Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. Exp. doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. (2020). It was first hypothesized that tropoelastin assembles in a head-to-tail manner similar to that of other ECM proteins such as collagen, which assembles into fibrils that subsequently associate laterally to form sheets and thicker fibers (Kadler, 2017). Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. [Epub ahead of print]. Ltd., which was sold to Allergan, now a division of AbbVie. Interestingly, the location and orientation of different domains that contacted each other during self-assembly was noted to be heterogeneous, resulting in head-to-head, tail-to-tail, head-to-tail, and lateral interactions (Tarakanova et al., 2019a). doi: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). Elastin makes up the majority of elastic fibers and is formed by the hierarchical assembly of its monomer, tropoelastin. Elastin: molecular description and function. The N-terminal head caps an extended coil region that consists of domains 2-18. Acta Biomater. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. Matrix Biol. 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. Adv. 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. 278, 4855348562. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Biophys. 33, 54685481. (2019). 149, 282289. 289, 14671477. Adv. (2015). HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). However, there are aspects of this model that warrant further investigation. 126, 283290. Chem. This process is reversible and thermodynamically controlled and does not require protein cleavage. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). (2015). Parameter, Testing, and Method. Fabricating organized elastin in vascular grafts. EDPs can modulate an array of signal pathways (Scandolera et al., 2016), but full-length tropoelastin does not trigger pathways through the ERC. 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). Acad. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. 10 Endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts produce tropoelastin during the late Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Elastic fibers are eventually formed after extensive cross-linking through a process termed maturation (Yeo et al., 2016). 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. Res. doi: 10.1016/j.bbagen.2017.07.020, Myers, B., Dubick, M., Last, J. J. Biol. Matrix Biol. Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Tropoelastin. 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). Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). 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. Structural changes and facilitated association of tropoelastin. 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. 82, 335340. Cross-linking domains are capable of modulating self-assembly when incorporated into peptides and biomaterials derived from tropoelastins hydrophobic domains. Res. 69, 89102. 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 . Chemistry 10, 31663176. Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. doi: 10.1016/j.matbio.2007.05.005, He, D., Miao, M., Sitarz, E. E., Muiznieks, L. D., Reichheld, S., Stahl, R. J., et al. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. 264, 88878891. The N-terminal head caps an extended coil region that consists of domains 218. Elastogenesis in human aorta: an electron microscopic study. Natl. Cooperativity between the hydrophobic and cross-linking domains of elastin. 126, 563574. doi: 10.1016/0378-1119(94)00848-m, McLaughlin, P. J., Chen, Q., Horiguchi, M., Starcher, B. C., Stanton, J. J. Cytochem. Developing elastic tissue. 26, 115124. Biochemistry of tropoelastin. 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". doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). J. Ultrastruct. Biochemistry 45, 99899996. Foster, J. This suggests a high level of conformational sampling during this phase of coacervation, indicating that the flexibility of tropoelastin plays a key role in assembly that may persist, to some extent, into later stages of assembly (Reichheld et al., 2020). doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). (2017). 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). Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. (2005). 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. Sci. The authors wrote and submitted this manuscript in response to an invitation by the Editor. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). 250, 9298. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. Int. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). To get started with texting, you will need: Your phone number 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). 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]. Pathol. Allergan Plc, a $15.9b provider of medical aesthetics, biosimilars, and over-the-counter pharmaceutical products will acquire Elastagen Pty Ltd., a provider of advanced tissue repair platform based on tropoelastin (gives tissue its elasticity) for $95m.The acquisition adds proprietary injectable products to Allergan's existing portfolio. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. Biosci. The importance of tropoelastins flexibility during self-assembly has also been examined in the light of natural allysine modifications, which condense to give cross-links within mature elastin (discussed further in the following section) (Ozsvar et al., 2019). Nature 437, 9991002. Acta 761, 1722. Biochim. 252, 351365. doi: 10.1006/jmbi.2000.3901, Baldock, C., Oberhauser, A. F., Ma, L., Lammie, D., Siegler, V., Mithieux, S. M., et al. Solving tropoelastins global structure (Baldock et al., 2011) allowed for 3D mapping on tropoelastin of the approximate locations of domains 10, 19, and 25, which were the first unequivocally cross-linked domains to be discovered (Brown-Augsburger et al., 1995). (2020). 220, 312324. 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. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. Proc. 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). Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. J. Mol. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). Thus, computational approaches can be considered as important means to complement wet bench experiments. Biochem. 27, 441450. J. Biol. (1965). Coarse-grained model of tropoelastin self-assembly into nascent fibrils. 260, 32553258. Fluor: Q4 Earnings Snapshot. Micron 41, 268272. doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Biosynthesis and nature of elastin structures. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Water structure and elastin-like peptide aggregation. J. Pathol. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. 4, 508524. 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). N. Y. Acad. (2006). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. doi: 10.1021/acs.biomac.8b01503, Rauscher, S., Baud, S., Miao, M., Keeley, F. W., and Poms, R. (2006). Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . 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). Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. 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. doi: 10.1021/bi981641y, Kozel, B. For this injection, the researchers used a new . 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). Fell muir lecture: collagen fibril formation in vitro and in vivo. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. 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). Chem. Homology models for domains 21-23 of human tropoelastin shed light on lysine crosslinking. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. 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. Delineation of unusual features in the 5-flanking region. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. A., and Rucker, R. B. J. Biol. 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). 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). Investig. Bull. In contrast, higher temperatures allow the breaking of the hydrogen bonds of the ordered water, dissipating the clathrate shells and permitting the association of the hydrophobic domains (Yeo et al., 2011).