ACS Biomater. Biochim. This phenomenon is supported by in vitro peptide studies, which note that increasing the space between PG motifs or removing prolines results in more ordered structures (Rauscher et al., 2006). FASEB J. doi: 10.1161/circimaging.117.007303, Prhashanna, A., Taylor, P. A., Qin, J., Kiick, K. L., and Jayaraman, A. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated . 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: 10.1038/nature04085. Coacervation of recombinant human tropoelastin is strongly influenced by the concentration of protein and NaCl and to a lesser extent on pH. 410, 317323. The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. 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. Matrix Biol. 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. We are very interested in the blend of biochemistry and cell biology, as well as the tissue engineering and regenerative medicine opportunities provided by this amazing elastic protein. Matrix Biol. (2006). (2018). U.S.A. 116, 20422051. 276, 3603536042. Thermal compaction of disordered and elastin-like polypeptides: a temperature-dependent, sequence-specific coarse-grained simulation model. Exon 26-coded polypeptide: an isolated hydrophobic domain of human tropoelastin able to self-assemble in vitro. The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. Acta Gen. Subj. (2018). Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. (1989). 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). 10, 441454. Biochemistry 8, 28332837. J. Hum. Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Elastin biomaterials in dermal repair. J. Struct. A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. 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). Biomaterials 127, 4960. Eng. 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. Acta Biomater. (2001). 15, 786801. doi: 10.1128/mcb.26.5.1700-1709.2006, Mecham, R. P. (1991). 289, 14671477. (2015). 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). For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. The full-atomistic model of tropoelastin was developed based on replica exchange molecular dynamics (REMD) simulations, an accelerated sampling method for molecular dynamics (Tarakanova et al., 2018). 16,17 We have previously shown that monomeric TE is utilized as a substrate by dermal fibroblasts in the formation of elastin fibroblasts in vitro, where Nature 437, 9991002. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). 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. A. 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). 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. Proc. 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: 10.1021/bi060289i, Tarakanova, A., and Buehler, M. J. Tropoelastin is a flexible molecule that retains its canonical shape. Proc. Mater. 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,". 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. This temperature is also known as the transition temperature. 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. Tropoelastins primary sequence is low in complexity and contains repetitive motifs. doi: 10.1016/j.micron.2009.11.003, Urban, Z., Hucthagowder, V., Schrmann, N., Todorovic, V., Zilberberg, L., Choi, J., et al. Trends towards maximal association are apparent when each of these parameters is varied. Lysinonorleucine. doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). doi: 10.1006/excr.1995.1321, Hinek, A., and Rabinovitch, M. (1994). 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). Transl. 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 . Front. J. Clin. Rev. (2017). PLoS One 7:e46130. Differential scanning calorimetry studies of the inverse temperature transition of the polypentapeptide of elastin and its analogues. Thus, computational approaches can be considered as important means to complement wet bench experiments. Allergan's Acquisition of Elastagen. 4, 508524. doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. EBP plays two roles in the assembly of elastin. Chemistry 10, 31663176. Biopolymers 20, 12471260. J. Biol. Biophys. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. By probing mutations in computational studies that resolve the atomistic structure of the molecule, the deduction of mechanisms associated with changes to functional roles of specific domains has become feasible, and a connection between local structures and biological performance can be established (Figure 2; Tarakanova et al., 2018). Matrix Biol. Biochemistry 37, 1461314622. 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. (2005). 10, 15321541. The business could generate net sales of approximately $7 to $8 billion in 2025 from $3.8 billion in 2017. Assembly proceeds from a nucleation event and undergoes elongation in a step-wise manner to form a multimer which can occur in a head-to-tail fashion (Wise et al., 2014). doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. (1995). 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 . Chem. Matrix Biol. 69, 89102. Lyophilized Powder. 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). In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). FEBS J. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. The smooth muscle cell. J. Mol. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). 126, 563574. (2006). Trends Biotechnol. (2005). 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). Biol. Elastin synthesis in arterial smooth muscle cell culture. The alignment of the tropoelastin aggregates . doi: 10.1006/jmbi.1995.0502, Yeo, G. C., Baldock, C., Tuukkanen, A., Roessle, M., Dyksterhuis, L. B., Wise, S. G., et al. 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. Elastin is extensively cross-linked and difficult to break apart into monomers even under harsh conditions, thus, initial strategies included feeding animals a copper deficient diet to prevent lysyl oxidase (LOX) cross-linking of tropoelastin; however, this proved inefficient and time consuming (Wise and Weiss, 2009; Tarakanova et al., 2018). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). 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. Sci. 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). 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). Arch. doi: 10.1016/s0945-053x(03)00014-3, Vrhovski, B., Jensen, S., and Weiss, A. S. (1997). Circ. Domain 36 of tropoelastin in elastic fiber formation. 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). 149, 282289. Forty tropoelastin molecules were subjected to simulations using a MARTINI-based coarse-grained model, integrated with an elastic network model (Tarakanova et al., 2019a). Investig. (2008). (2018). Biomacromolecules 18, 599609. 19:e1800250. doi: 10.1016/j.matbio.2009.10.003, Tu, Y., Wise, S. G., and Weiss, A. S. (2010). 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). Its hydrophobic (pink) and cross-linking (blue) domains consist of repetitive motifs that contribute uniquely to elastin assembly. J. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. These interactions trigger a wide range of processes including wound healing, elastogenesis and maintenance of stemness (Yeo and Weiss, 2019). 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. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Biochem. We are making enrolling in text alerts easier than ever. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Unlike other companies that use paid endorsements and questionable data, NULASTIN science is proven by 3rd party clinical evaluation. The hydrophobic domains are involved in coacervation and the hydrophilic domains are used for cross-linking. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors. Unsubstituted models are also critical to understanding self-assembly. Biopolymers 103, 563573. Micron 41, 268272. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Struct. 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). Tropoelastin #5052. Biophys. Med. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. Figure 3. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. 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". Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). doi: 10.1021/acsbiomaterials.6b00564, Yeo, G. C., Keeley, F. W., and Weiss, A. S. (2011). Chem. J. Biol. J. Biol. Synthesis and structural studies of a pentapeptide sequence of elastin. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Biol. FEBS Lett. J. Ultrastruct. doi: 10.1007/978-1-4684-9093-0_25, Scandolera, A., Odoul, L., Salesse, S., Guillot, A., Blaise, S., Kawecki, C., et al. doi: 10.1016/s0022-5320(83)80021-5, Broekelmann, T. J., Kozel, B. While the clinical stage tropoelastin platform provides multiple opportunities for aesthetics, scar remodelling and tissue repair, it also has the . Res. Synthesis and properties of crosslinked recombinant pro-resilin. For example, their inclusion in peptides derived from hydrophobic domains confers decreased times taken for self-assembly, most likely due to their favorable interaction with aqueous solvent (Miao et al., 2003). into 200 nm then 12 m spherules, which eventually grow and stabilize into spherules 26 m in diameter (Clarke et al., 2006; Kozel et al., 2006; Tu and Weiss, 2010; Tu et al., 2010). This content is for members only. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. U.S.A. 84, 56805684. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. A., and Rucker, R. B. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. Cell Biol. doi: 10.1021/bi00835a021, Gray, W. R., Sandberg, L. B., and Foster, J. 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. Integrins are a major class of cell surface receptor family, of which tropoelastin has been found to interact with two types: v3 (Rodgers and Weiss, 2004) and v5. 252, 351365. doi: 10.1002/bip.1981.360200611. A comprehensive map of human elastin cross-linking during elastogenesis. Biosynthesis and nature of elastin structures. 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. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). In addition to its involvement in molecular elasticity, the flexibility of tropoelastin also a key requirement for self-assembly into elastin, with mutations that perturb this having detrimental effects on tissue (Yeo et al., 2016, 2017). 589(19 Pt A), 24772486. FEBS J. 220, 312324. Background: Elastin is an essential component of the dermis, providing skin with elasticity and integrity. (1987). U.S.A. 112, E4408E4415. Cell Biol. [Epub ahead of print]. 207, 8796. Fibulin-4 and -5, but not fibulin-2, are associated with tropoelastin deposition in elastin-producing cell culture. doi: 10.1016/j.matbio.2006.08.258, Clarke, A. W., Arnspang, E. C., Mithieux, S. M., Korkmaz, E., Braet, F., and Weiss, A. S. (2006). Chem. Albert, E. N. (1972). 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). AW gratefully acknowledges NHMRC funding (Ref: 1195827). (2012). U.S.A. 115, 73387343. Int. Cooperativity between the hydrophobic and cross-linking domains of elastin. Molecular model for elastin structure and function. The hydrophobic domain 26 of human tropoelastin is unstructured in solution. Bonnans, C., Chou, J., and Werb, Z. (2017). doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. Chem. Natl. Elastagen's technology is based on human tropoelastin . Sci. 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). 41, 494497. 9:643110. doi: 10.3389/fbioe.2021.643110. (2019). Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. 98, 416. 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 scars, stretch marks, aesthetic skin repair and wound repair. Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. 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. 282, 1248412491. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), Italy, Washington University in St. Louis, United States. Hogan Lovells represented Elastagen Pty Ltd. on the deal. Unlike hydrophobic domains, cross-linking domains in isolation are unable to self-assemble; thus, they have been studied in the context of the cross-linking of elastin-derived biomaterials (Annabi et al., 2017; Yue et al., 2017). Acad. The resultant bending motion rather than scissors-twist motion that stemmed from this stabilization highlights the mutants diminished flexibility as a key driver of impaired fiber assembly in cutis laxa (Tarakanova et al., 2018). 3:100016. doi: 10.1016/j.mtbio.2019.100016, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. (2014). Thus, the current computational model unifies the global and regional characteristics of tropoelastin, inferring mechanisms that complement observed experimental phenomena. doi: 10.1016/s1357-2725(98)00098-3, Duca, L., Blanchevoye, C., Cantarelli, B., Ghoneim, C., Dedieu, S., Delacoux, F., et al. 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. Fluor: Q4 Earnings Snapshot. 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). Acad. Simul. (2018). U.S.A. 110, 28522857. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). Chem. Sci. Tropoelastins domains each arise from single exons of the ELN gene. Acta 303, 363369. (1973). For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Biol. Sci. Elastagen is an exciting clinical-stage company with an advanced tissue repair platform based on tropoelastin. The amino acid sequence of domain 36 is unique; furthermore, its sequence confers a positively charged C-terminus comprising lysines between positively charged arginines, forming a RKRK sequence (Vrhovski et al., 1997). doi: 10.1016/s0003-9861(02)00719-1, Muiznieks, L. D., Reichheld, S. E., Sitarz, E. E., Miao, M., and Keeley, F. W. (2015). Developmental changes of tropoelastin synthesis by rat pulmonary fibroblasts and effects of dexamethasone. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). J. Biol. 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). 1, 2 Elastogenesis, the process of elastin formation, mainly occurs during the fetal and early neonatal development of organs such as blood vessels, lungs, and skin. Natl. Chem. I thank the Elastagen team for their hard work and dedication in developing our innovative tropoelastin product pipeline and look forward to working with Allergan to take these products to market., Commenting on the transaction, Elastagens founding scientist Prof Anthony Weiss added:Our technology has come a long way from the lab bench at the University of Sydney towards developing products for patients around the world. To get started with texting, you will need: Your phone number Delineation of unusual features in the 5-flanking region. 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. 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). Fed. 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. Ltd., which was sold to Allergan, now a division of AbbVie. Tropoelastin is a spring-like molecule that is extremely extensible prior to cross-linking. Future investigations will allow the bridging of the gap between mesoscale simulations and microscopically observed coacervation (Clarke et al., 2006). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Localizing alpha-helices in human tropoelastin: assembly of the elastin puzzle. doi: 10.1074/jbc.M113.533893, Reiersen, H., and Rees, A. R. (2000). doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). J. Mol. doi: 10.1002/jcp.20546, Kozel, B. Pathol. 58, 270277. Cell Biol. 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). Biol. Domain 26 of tropoelastin plays a dominant role in association by coacervation. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. 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. Genet. Powered by Madgex Job Board Software. The lysines of domain 15 and 17 are believed to play key roles in this interaction. 289, 1005710068. (2015). 260, 32553258. (1981). doi: 10.1002/chem.200305661. The authors wrote and submitted this manuscript in response to an invitation by the Editor. FEBS J. Free energy determinants of secondary structure formation: I. alpha-Helices. Sci. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Tropoelastin has 2 alternating domains: (1) hydrophilic, cross-linked, domains rich in Lys and Ala; and (2) hydrophobic domains (responsible for elasticity) rich in Val, Pro, and Gly, which often occur in repeats of VPGVG or VGGVG. Matrix Biol. 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). February 14, 2018 Michael Patrini. Elastic fibers are composed of approximately 90% elastin, whilst the remaining components are primarily comprised of fibrillin glycoproteins (Mecham, 1991). 3, 28322844. Proc. 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 42, 1334713362. Allysine modifications perturb tropoelastin structure and mobility on a local and global scale. Partridge, S. M. (1966). doi: 10.1016/j.jsb.2005.02.005, Martin, S. L., Vrhovski, B., and Weiss, A. S. (1995). Water structure and elastin-like peptide aggregation. Matrix Biol. Chem. J. Biomol. Acta Histochem. Today Biol. Macromol. 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. Studies on the reduction of elastin. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company.