U.S.A. 110, 28522857. Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). (2019). The hydrophobic domains contain repetitions and variations of Val-Pro-Gly-Val-Gly motifs (Figure 1), resulting in the aforementioned low complexity of sequence (Foster et al., 1973; Gray et al., 1973). doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Biopolymers 107:e23007. 249, 997998. 26, 524540. J. Hum. 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). Today Biol. Rep. 8, 116. Lyophilized Powder. Mol. Rev. 87, 18281834. Elastagens revolutionary recombinant human tropoelastin, is identical to that present in human tissue and has many clinical applications, including effective breakthrough treatments for acne scars, stretch marks, aesthetic skin repair and wound repair. For this injection, the researchers used a new . Tropoelastin Improves Post-Infarct Cardiac Function 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. (2016). 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. 85, 593605. Macromol. For more information, visit Allergans website atwww.Allergan.com. Elastagen Pty Ltd, a clinical stage company developing medical device products based on recombinant tropoelastin, today announced. Below the coil is a flexible hinge region made up of domains 2024, which are directly adjacent to the bridge regions of domains 2526. (1983). Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. Bonnans, C., Chou, J., and Werb, Z. Cell Res. Elastagen is creating injectables using recombinant human tropelastin, a substance that's crucial for producing elastin fibers in the skin. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. Arch. Trifluoroethanol may form a solvent matrix for assisted hydrophobic interactions between peptide side chains. 149, 282289. Fibrillin-1 interactions with heparin. 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. Foster, J. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Chem. 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 . Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. U.S.A. 109, 28782883. Pathol. J. Mol. doi: 10.1016/j.actbio.2013.08.003, Wu, W. J., and Weiss, A. S. (1999). Domains 12 to 16 of tropoelastin promote cell attachment and spreading Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. Natl. Chem. Nat. Molecular modeling of protein materials: case study of elastin. (2005). doi: 10.1038/nature06669, Cox, B. Similar to other ECM proteins, such as collagen, tropoelastin covalently cross-links via its lysines. (2009). The human ELN gene is located on the long arm of chromosome 7q11.2 and comprises of 34 exons nestled between lengthy introns (Indik et al., 1987, 1989; Bashir et al., 1989). [Epub ahead of print]. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Chem. J. Biol. Mechanism of helix induction by trifluoroethanol: a framework for extrapolating the helix-forming properties of peptides from trifluoroethanol/water mixtures back to water. Matrix Biol. J. Struct. 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). The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966). A. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). doi: 10.1007/s004030050227, Tamburro, A. M., Bochicchio, B., and Pepe, A. Completion of the transition is subject to customary closing conditions, including review by Australias Foreign Investment Review Board. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). Clinical Relevance of Elastin in the Structure and Function of Skin Upon secretion tropoelastin has the propensity to self-aggregate through a process known as coacervation. Albert, E. N. (1972). Stages in tropoelastin coalescence during synthetic elastin hydrogel formation. Matrix Biol. Tropoelastin #5052. Elastogenic cells, such as fibroblasts (Mecham et al., 1985) and smooth muscle cells (Narayanan et al., 1976), synthesize and secrete tropoelastin. Eur. 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. Med. Imaging 11:e007303. doi: 10.1073/pnas.1111615108, Yeo, G. C., Baldock, C., Wise, S. G., and Weiss, A. S. (2017). Human tropoelastin improves rat heart function postmyocardial infarction and could potentially be used to treat heart failure. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). 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. 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). Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Exp. Water structure and elastin-like peptide aggregation. 280, 4093940947. Proline-poor hydrophobic domains modulate the assembly and material properties of polymeric elastin. doi: 10.1016/j.tibtech.2019.08.005, Wise, S. G., and Weiss, A. S. (2009). Matrix Biol. 69, 89102. Glycosaminoglycans (GAGs) are negatively charged, linear polysaccharides, which can be either sulfated [heparan sulfate (HS) or chondroitin sulfate] or non-sulfated (hyaluronic acid). Biochim. 278, 1849118498. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed Sequence and structure determinants for the self-aggregation of recombinant polypeptides modeled after human elastin. Computational models have also been leveraged to pinpoint the molecular consequences of synthetic and disease mutations of tropoelastin. The Weiss Lab's research focuses on the use of human tropoelastin in tissue assembly and wound repair. Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). doi: 10.1016/j.matbio.2009.07.003, Mithieux, S. M., Wise, S. G., Raftery, M. J., Starcher, B., and Weiss, A. S. (2005). 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. Elastin - an overview | ScienceDirect Topics Reichheld, S. E., Muiznieks, L. D., Keeley, F. W., and Sharpe, S. (2017). Tropoelastin - an overview | ScienceDirect Topics Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. (2019). Chem. Colloid Interface Sci. Adv. Pathol. 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. In addition to interacting with tropoelastin, fibulin-4 and -5 are capable of also binding LOX and fibrillin-1 and, thus, have key roles in facilitating elastogenesis (Hinderer et al., 2015). 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. Sci. J. Pathol. 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). Proc. 284, 22162230. Chemistry 10, 31663176. Invest. Subtle balance of tropoelastin molecular shape and flexibility The hydrophobic domain 26 of human tropoelastin is unstructured in solution. 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. The smooth muscle cell. Tropoelastins domains each arise from single exons of the ELN gene. Coacervation characteristics of recombinant human tropoelastin 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). Proc. Synthesis and structural studies of a pentapeptide sequence of elastin. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. Structure 14, 16671676. The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from Wellcome Trust (203128/Z/16/Z). Res. Primary structure of porcine tropoelastin. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. (2018). Biopolymers 103, 563573. (2020). Biochemistry of tropoelastin. 22, 109121. doi: 10.1073/pnas.1701877114, Reichheld, S. E., Muiznieks, L. D., Lu, R., Sharpe, S., and Keeley, F. W. (2019). The hydrophobic domains contain aliphatic amino acids with proline variations that provide flexibility and the ability to assemble into higher order structures. Elastases can be in the form of serine- (e.g., Ela-2), cysteine- (e.g., cathepsin I), or matrix metalloproteinases (MMP-2, -7, -9, and -12), and bioactive peptides include the VGVAPG peptide. J. Biochem. Founder, Elastagen Pty Ltd (sold to Allergan/AbbVie . J. Biol. Biochemistry 37, 1461314622. Cell Biol. Elastin - Wikipedia 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. 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). 43, 131138. 9:643110. doi: 10.3389/fbioe.2021.643110. Sci. Biochemistry 45, 99899996. 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). doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). 58, 270277. Tropoelastin: a versatile, bioactive assembly module - PubMed doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). Allergan Highlights Key Growth Drivers for Medical Aesthetics Characterization of an unusual tropoelastin with truncated C-terminus in the frog. doi: 10.1074/jbc.M104985200, Toonkool, P., Jensen, S. A., Maxwell, A. L., and Weiss, A. S. (2001). Remodelling the extracellular matrix in development and disease. J. Biol. Res. Proc. Int. Received: 17 December 2020; Accepted: 08 February 2021;Published: 25 February 2021. Nature 437, 9991002. Tropoelastin. 289, 14671477. J. Clin. Biomacromolecules 21, 35233538. doi: 10.1073/pnas.1014280108. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. CB gratefully acknowledges BBSRC funding (Ref: BB/R008221/1). (2017). Tropoelastin is a flexible molecule that retains its canonical shape. Elastin is a critical skin protein consisting of crosslinked tropoelastin. Targeted modulation of tropoelastin structure and assembly. J. Biol. Med. The elastin receptor complex: a unique matricellular receptor with high anti-tumoral potential. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. How to Get LONGER Eyelashes - Guaranteed | NULASTIN Biopolymers 20, 12471260. Coacervation is an endothermic, entropically favorable process through which tropoelastin monomers self-assemble into higher order n-mer structures. Figure 1. 432, 57365751. Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global biopharmaceutical company. This content is for members only. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. 10:034102. doi: 10.1088/1748-6041/10/3/034102, Hinek, A., Keeley, F. W., and Callahan, J. Isolation and characterization of crosslinked peptides from elastin. The computational model uncovered the contributions of each molecular region to the flexibility of the molecule. Tropoelastin: a novel marker for plaque progression and instability. Matrix Biol. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. 28, 379382. Tropoelastin aggregates at physiological temperature due to interactions between hydrophobic domains in a process called coacervation. Molecular model of human tropoelastin and implications of associated mutations. Our understanding of key aspects of the assembly process have been unclear due to the intrinsic properties of elastin and tropoelastin that render them difficult to study. doi: 10.1016/j.jsb.2004.11.005, Muiznieks, L. D., Jensen, S. A., and Weiss, A. S. (2003). Tropoelastins sequence and domain arrangement. Elastin synthesis and fiber assembly. 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. Acad. 120, 419426. Frontiers | Tropoelastin and Elastin Assembly doi: 10.1016/j.str.2006.09.008, Rauscher, S., and Pomes, R. (2017). (2005). 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. The self-assembly properties and nanostructure of these extra teleost isoforms are yet to be investigated. 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). Chem. Biol. doi: 10.1172/jci115204, Sherratt, M., Wess, T. J., Baldock, C., Ashworth, J., Purslow, P., Shuttleworth, C., et al. 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. 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. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). 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). For Allergan, contact: Lisa Brown 1-862-261-7320, 1985 - 2023 BioSpace.com. The company is particularly pointing to usage in the treatment of acne scars, stretch marks, aesthetic skin repair and surgical wound repair. 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). Implications for tissue specificity and durability of elastic tissue. Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). III. J. Biol. Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. doi: 10.1002/bip.1981.360200611. Biol. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Am. 41, 494497. 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. Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Biochemistry 45, 95189530. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. This deduction has been corroborated by the observation that tropoelastin with multiple allysine modifications displays conformational sampling comparable to that of the wild-type molecule, suggesting it is more likely to readily participate in self-assembly. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. 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). For more information, visit Elastagens website atwww.elastagen.com. Patient Homepage | Accredo J. Biol. 293, 1510715119. Ann. Biochimie 86, 173178. Structural changes and facilitated association of tropoelastin. Production of recombinant human tropoelastin: Characterization and doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. J. Biol. The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit. 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".