(2019). doi: 10.1096/fj.201801860RR, Schrader, C. U., Heinz, A., Majovsky, P., Karaman Mayack, B., Brinckmann, J., Sippl, W., et al. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. Elastin combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. 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). J. Biochem. Elastin is one of the most abundant proteins in your body. J. All authors contributed to writing and editing the review. Natl. Cell Biol. Anal. Exp. Powered by Madgex Job Board Software. 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. 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. 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. doi: 10.1111/j.1432-1033.1997.00092.x, Vrhovski, B., and Weiss, A. S. (1998). doi: 10.1073/pnas.1801205115, Tarakanova, A., Yeo, G. C., Baldock, C., Weiss, A. S., and Buehler, M. J. Biol. eLife 6:e26526. 275, 2844928454. 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). Copyright 2021 Ozsvar, Yang, Cain, Baldock, Tarakanova and Weiss. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. 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. 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. Struct. Figure 2. Elastin synthesis and fiber assembly. Cross-linking domains can be subdivided into KP or KA domains, which denote the amino acids (proline or alanine, respectively) that are adjacent to the lysines (Figure 1). Tropoelastin is typically used as a thin coating on tissue culture surfaces. (2014). Biochem. Trends towards maximal association are apparent when each of these parameters is varied. doi: 10.1016/0304-4165(83)90357-4, Narayanan, A. S., Sandberg, L. B., Ross, R., and Layman, D. L. (1976). Biochim. 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. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. Rev. Sci. Rep. 8, 116. 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: 10.1111/iep.12224, Kentsis, A., and Sosnick, T. R. (1998). (2006). [Epub ahead of print]. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. Increased cyclic GMP levels lead to a stimulation of elastin production in ligament fibroblasts that is reversed by cyclic AMP. 258, 118. J. Biol. doi: 10.1083/jcb.126.2.563, Hu, Q., Reymond, J. L., Pinel, N., Zabot, M. T., and Urban, Z. 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 . doi: 10.1021/bi0610092, Cordier, P., Tournilhac, F., Souli-Ziakovic, C., and Leibler, L. (2008). 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. Pathol. Conformational transitions of the cross-linking domains of elastin during self-assembly. Elastic fibers are present in the extracellular matrix (ECM) of vertebrate tissues, such as the skin, lungs, cardiovascular system, cartilage, and tendons. J. (1977). Implications for tissue specificity and durability of elastic tissue. 280, 3052630537. 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). Am. Elastin binding protein and FKBP65 modulate in vitro self-assembly of human tropoelastin. 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). Lysinonorleucine. (1973). 207, 8796. Direct observation of structure and dynamics during phase separation of an elastomeric protein. 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. 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. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. FEBS Lett. 250, 9298. Domain 26 of tropoelastin plays a dominant role in association by coacervation. (1995). Unsubstituted models are also critical to understanding self-assembly. 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). A., Rongish, B. J., Czirok, A., Zach, J., Little, C. D., Davis, E. C., et al. 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). Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Elastin-like polypeptides as models of intrinsically disordered proteins. The study is designed to evaluate the efficacy of two formulations of a cross-linked tropoelastin matrix given the product codes ELAPR002f (collectively referred to as ELAPR or ELAPR002) for the treatment of rolling atrophic acne scars when administered as intradermal implants. doi: 10.1021/bi9707133, MacEwan, S. R., Weitzhandler, I., Hoffmann, I., Genzer, J., Gradzielski, M., and Chilkoti, A. 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. 286, 35943610. 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). 281, 2375723765. With the acquisition, Allergan will begin developing a new line that incorporates tropoelastin in the injectable's formula. U.S.A. 115, 73387343. Proc. Synthesis and structural studies of a pentapeptide sequence of elastin. Biochemistry 45, 99899996. The ability to stretch and recoil arises from the biochemical properties of elastins monomer, tropoelastin (discussed below). Tropoelastin is a precursor protein of elastin, and is composed of hydrophilic (lysine, valine and proline) and hydrophobic (glycine, valine and proline) domains. Injectable biomaterial compositions formed from tropoelastin for tissue repair and restoration. Tropoelastin massively associates during coacervation to form quantized protein spheres. They can be categorized as either hydrophobic or cross-linking based on their functionality and amino acid content (Figure 1). 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). 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). The hydrophobic domains vary in length, with the majority of the shorter (95 residues) domains occurring near the N-terminus, while the longer (up to 55 residues) domains are found within tropoelastins central and C-terminal regions (Indik et al., 1989). Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. J. Mol. 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). For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). Stages of hierarchical assembly of elastic fibers. Exp. Acad. 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). Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). Elastogenesis in human aorta: an electron microscopic study. 252, 351365. Trends Biotechnol. Nature 437, 9991002. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Calorim. Res. Mater. AT acknowledges support from University of Connecticuts Institute for Collaboration on Health, Intervention, and Policy Faculty Research Seed Grant. Hydrophobic domains of human tropoelastin interact in a context-dependent manner. Cell Biol. Acad. doi: 10.1038/sj.jid.5700047, Indik, Z., Yeh, H., Ornstein-Goldstein, N., Kucich, U., Abrams, W., Rosenbloom, J. C., et al. In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). Matrix 12, 156162. The spherules grow in size and are deposited onto the microfibril scaffold where they fuse into fibrillar structures (Sherratt et al., 2001). Protein Eng. 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. 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). J. Hum. 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. Adv. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints . 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). Mater. Intracellularly, EBP is associated with tropoelastin after the release of the signal peptide and acts as a chaperone to prevent self-aggregation and proteolysis as it transported to the cell membrane, after which EBP is then recycled and serves as a reusable shuttle protein (Hinek et al., 1995). Natl. U.S.A. 84, 56805684. Bioeng. 167, 94103. 120, 419426. Tropoelastins hydrophobic domains are predominantly responsible for the random coil content of the monomer, and are the result of the unique pairing of proline and glycine pairs that are interspersed throughout the majority of hydrophobic domains (Rauscher and Pomes, 2017). Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Matrix Biol. Micron 32, 185200. doi: 10.1016/j.jmb.2020.08.023, Luan, C. H., Harris, R., Prasad, K. U., and Urry, D. W. (1990). U.S.A. 112, E4408E4415. Sci. Tropoelastin is a flexible molecule that retains its canonical shape. An electron microscopic study. Aaron, B., and Gosline, J. Nature 246, 461466. J. Mol. (2014). "We believe it's in the best strategic interest of the company to make this move, which supports Caterpillar's strategy for profitable . 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. Latent TGF- binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. doi: 10.1083/jcb.68.3.411, Noda, K., Dabovic, B., Takagi, K., Inoue, T., Horiguchi, M., Hirai, M., et al. Thus, computational approaches can be considered as important means to complement wet bench experiments. 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 . More recently, the computational model of tropoelastin has been leveraged to characterize higher-order structures and probe self-assembly (Tarakanova et al., 2019a). doi: 10.1016/s0021-9258(19)43030-5, Dandurand, J., Samouillan, V., Lacabanne, C., Pepe, A., and Bochicchio, B. Elastin: molecular description and function. 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. A., Gray, W. R., and Franzblau, C. (1973). Biopolymers 20, 12471260. A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. doi: 10.1203/00006450-199010000-00015, Nonaka, R., Sato, F., and Wachi, H. (2014). Ltd., which was sold to Allergan, now a division of AbbVie. Fell muir lecture: collagen fibril formation in vitro and in vivo. Elastin biomaterials in dermal repair. J. Clin. Dissection of human tropoelastin: exon-by-exon chemical synthesis and related conformational studies. Int. doi: 10.1080/07391102.1992.10508661, Tamburro, A. M., Pepe, A., and Bochicchio, B. Vallet, S. D., Miele, A. E., Uciechowska-Kaczmarzyk, U., Liwo, A., Duclos, B., Samsonov, S. A., et al. Biomaterials 139, 163171. J. Biochem. Banded fibers in tropoelastin coacervates at physiological temperatures. 26, 524540. 289, 1005710068. Another region of note is domain 36, which contains lysines but does not participate in cross-linking (Hedtke et al., 2019). 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. 282, 1248412491. Integrin alpha v beta 3 binds a unique non-RGD site near the C-terminus of human tropoelastin.