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• W2000922221 abstract "Jensen et al. report the crystal structure of a human fibrillin-1 hybrid domain in this issue of Structure. This domain is found exclusively in the fibrillin/latent transforming growth factor-β binding protein superfamily and shares structural features with two other domains in these proteins, the TB/8-Cys and the cbEGF domains. Jensen et al. report the crystal structure of a human fibrillin-1 hybrid domain in this issue of Structure. This domain is found exclusively in the fibrillin/latent transforming growth factor-β binding protein superfamily and shares structural features with two other domains in these proteins, the TB/8-Cys and the cbEGF domains. Fibrillins are extended 350-kDa extracellular matrix proteins that constitute the backbone of microfibrils, large molecular machines found in elastic and nonelastic tissues. Microfibrils play important roles in the biogenesis of elastic fibers, in conferring limited elasticity to tissues, and in the regulation of bioavailability of transforming growth factor-β superfamily members. Similar to other matrix glycoproteins, fibrillins display a tandemly arrayed domain organization, with each domain representing an individual folding unit. Fibrillins, together with the latent transforming growth factor-β binding proteins (LTBPs), form a superfamily of proteins characterized by the presence of two unique domains: the transforming growth factor-β binding protein-like (TB or 8-Cys) domains, and the hybrid (hyb) domains (Figure 1). The limitations for high resolution structural studies of the full-length fibrillins are their large molecular mass combined with a relatively low solubility, the extremely high number of cysteine residues (361 in fibrillin-1, equivalent to 12.6%), almost all engaged in disulfide-bridges, and the extensive post-translational modifications, including N-glycosylation (Figure 1). However, it has been demonstrated that individual domains of fibrillin-1 or arrays of a few adjacent domains can be efficiently expressed in bacterial systems and refolded in vitro into correctly folded proteins (Knott et al., 1996Knott V. Downing A.K. Cardy C.M. Handford P. J. Mol. Biol. 1996; 255: 22-27Crossref PubMed Scopus (96) Google Scholar). Using this experimental approach, high resolution structures of fibrillin-1 calcium-binding epidermal growth factor-like (cbEGF) domains and TB/8-Cys domains have been solved successfully (Downing et al., 1996Downing A.K. Knott V. Werner J.M. Cardy C.M. Campbell I.D. Handford P.A. Cell. 1996; 85: 597-605Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, Lee et al., 2004Lee S.S. Knott V. Jovanovic J. Harlos K. Grimes J.M. Choulier L. Mardon H.J. Stuart D.I. Handford P.A. Structure. 2004; 12: 717-729Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The hyb1 domain in fibrillins mediates interactions with fibulin-2, −4, and −5, as well as with LTBP-1 and −4 (El-Hallous et al., 2007El-Hallous E. Sasaki T. Hubmacher D. Getie M. Tiedemann K. Brinckmann J. Batge B. Davis E.C. Reinhardt D.P. J. Biol. Chem. 2007; 282: 8935-8946Crossref PubMed Scopus (87) Google Scholar, Ono et al., 2009Ono R.N. Sengle G. Charbonneau N.L. Carlberg V. Bachinger H.P. Sasaki T. Lee-Arteaga S. Zilberberg L. Rifkin D.B. Ramirez F. et al.J. Biol. Chem. 2009; (in press. Published online April 6, 2009)https://doi.org/10.1074/jbcM809348200Crossref Google Scholar). In addition, it was shown that this domain participates in intermolecular disulfide-bond formation during microfibril assembly (Reinhardt et al., 2000Reinhardt D.P. Gambee J.E. Ono R.N. Bächinger H.P. Sakai L.Y. J. Biol. Chem. 2000; 275: 2205-2210Crossref PubMed Scopus (66) Google Scholar). No functional assignments have been delineated for the hyb2 domain in fibrillins. The initial primary sequence analysis of the TB/8-Cys, hyb, and cbEGF domains revealed similarities of the hyb domains' N termini with the N terminus of TB/8-Cys domains, and of the hyb domains' C termini with the C terminus of cbEGF domains (Corson et al., 1993Corson G.M. Chalberg S.C. Dietz H.C. Charbonneau N.L. Sakai L.Y. Genomics. 1993; 17: 476-484Crossref PubMed Scopus (219) Google Scholar). With the new high resolution (1.8 Å) crystal structure of a hyb domain from human fibrillin-1 (hyb2) reported by Jensen et al., 2009Jensen S.A. Iqbal S. Lowe E.D. Redfield C. Handford P.A. Structure. 2009; 17 (this issue): 759-768Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, it is now clear that these similarities in the primary sequence are fully reflected in the structure, proving that the hyb domain is indeed an evolutionary “hybrid” between TB/8-Cys and cbEGF domains. The overall structure of hyb2 flanked by cbEGF9 and cbEGF10 is similar to the structure of the TB/8-Cys domains in regard to the positions of characteristic side chains. In the central α-helical region of both domains, the “Cys-Cys-Cys” motif of the TB/8-Cys domain and the corresponding “Cys-Cys” motif in hyb2 are found in similar locations. In addition, a conserved cis-proline is placed in a corresponding structural region in both domains. In contrast to the TB/8-Cys structure, the hyb2 domain is missing a second α-helical stretch toward its C-terminal end. Another elementary difference between the two domains was found in the disulfide-bond patterns. Both domains contain eight cysteine residues; however, the hyb2 domain lacks one of the three cysteines in the “Cys-Cys-Cys” motif of the TB/8-Cys domain, but has two cysteine residues in its C terminus as opposed to one. These differently positioned cysteine residues result in a 1-3, 2-5, 4-6, 7-8 disulfide-bond pattern in the hyb domain, versus a 1-3, 2-6, 4-7, 5-8 pattern characteristic for the TB/8-Cys domain. In this context it will be interesting to determine the structure of the hyb1 domain of fibrillin-1, which contains an additional cysteine residue at position 204 and consequently has one unpaired cysteine. This extra cysteine residue in the hyb1 domain is conserved between all fibrillins and between all species. Hyb domains in LTBPs, on the other hand, do not have such an extra cysteine residue. Biochemical data previously suggested that cysteine 204 of fibrillin-1 occurs as a free thiol on the surface of the molecule, making it an ideal candidate for intermolecular crosslink formation (Reinhardt et al., 2000Reinhardt D.P. Gambee J.E. Ono R.N. Bächinger H.P. Sakai L.Y. J. Biol. Chem. 2000; 275: 2205-2210Crossref PubMed Scopus (66) Google Scholar). Molecular modeling of the hyb1 domain of fibrillin-1, based on the experimentally determined hyb2 coordinates presented in Jensen et al., 2009Jensen S.A. Iqbal S. Lowe E.D. Redfield C. Handford P.A. Structure. 2009; 17 (this issue): 759-768Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, supports this proposed role for the unpaired cysteine. The affinity for calcium binding to cbEGF domains in fibrillin-1 depends strongly on the nature of the inter-domain interfaces between adjacent domains. These contacts can modulate the affinity for calcium over a wide range (dissociation constants from nanomolar to millimolar). The cbEGF domains directly downstream of the TB/8-Cys domains frequently bind calcium with very high affinity attributed to hydrophobic domain interactions between the TB/8-Cys and the cbEGF domains (Jensen et al., 2005Jensen S.A. Corbett A.R. Knott V. Redfield C. Handford P.A. J. Biol. Chem. 2005; 280: 14076-14084Crossref PubMed Scopus (30) Google Scholar). In Jensen et al., 2009Jensen S.A. Iqbal S. Lowe E.D. Redfield C. Handford P.A. Structure. 2009; 17 (this issue): 759-768Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, the authors demonstrate that the cbEGF domains succeeding the hyb1 and hyb2 domains of fibrillin-1 also bind calcium with very high affinity with dissociation constants in the low nanomolar range, which is again explained by the extensive domain interactions at least observed between hyb2 and cbEGF10. Under physiological calcium concentrations (∼1.5 mM), the region around hyb2 adopts a near linear shape. Together with previously published structural data available for the TB/8-Cys domains and several cbEGF domains in their natural domain context, the authors predict the region between cbEGF3 and cbEGF43 (i.e., the majority of the fibrillin-1 molecule) to form an extended structure, as suggested by low resolution methods that include electron microscopy after rotary shadowing (Sakai et al., 1991Sakai L.Y. Keene D.R. Glanville R.W. Bächinger H.P. J. Biol. Chem. 1991; 266: 14763-14770Abstract Full Text PDF PubMed Google Scholar). This information will be very useful to validate existing models for fibrillin organization in microfibrils and to correlate the structure with specific functions. To fully understand the structure, macromolecular organization, and, ultimately, the functions of fibrillins, it will be necessary to solve the structure of (1) the proline/glycine-rich domains in fibrillins, (2) the N- and C-terminal unique domains, (3) larger contiguous portions of the proteins, (4) functional protein and self-interaction sites, and (5) fully assembled fibrillin-1 aggregates giving rise to microfibrils. These are challenges for the future. For now, the fibrillin-1 hyb2 structure is one more piece added to the fibrillin puzzle. We thank Ryan Kirschner for critical reading of the manuscript. Structure and Interdomain Interactions of a Hybrid Domain: A Disulphide-Rich Module of the Fibrillin/LTBP Superfamily of Matrix ProteinsJensen et al.StructureMay 13, 2009In BriefThe fibrillins and latent transforming growth factor-β binding proteins (LTBPs) form a superfamily of structurally-related proteins consisting of calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with 8-cysteine-containing transforming growth factor β-binding protein-like (TB) and hybrid (hyb) domains. Fibrillins are the major components of the extracellular 10–12 nm diameter microfibrils, which mediate a variety of cell-matrix interactions. Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 Å resolution. Full-Text PDF Open Access" @default.
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• W2000922221 title "One More Piece in the Fibrillin Puzzle" @default.
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