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Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins.

Jensen SA, Iqbal S, Lowe ED, Redfield C, Handford PA - Structure (2009)

Bottom Line: Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 A resolution.Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding.These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, UK.

ABSTRACT
The fibrillins and latent transforming growth factor-beta 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 beta-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 A resolution. The hybrid domain fold is similar, but not identical, to the TB domain fold seen in previous fibrillin-1 and LTBP-1 fragments. Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding. These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

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Comparison of Hyb2 and TB4 Domain Structures(A) Superposition of cbEGF9-hyb2-cbEGF10 onto the previously determined structure of fibrillin-1 fragment cbEGF22-TB4_cbEGF23 (Lee et al., 2004) showing the overall similarity of the structures.(B) Superpostion of individual domains of cbEGF9-hyb2-cbEGF10 onto the corresponding regions of cbEGF22-TB4-cbEGF23 indicated that differences in the structures were largely due to small differences seen in the interdomain packing interactions of the different constructs.(C and D) Domain hyb2 (C) has secondary structure elements similar to those seen in TB4 (D) (Lee et al., 2004). A conserved tryptophan (cyan spheres in the 3D models) is involved in forming the hydrophobic core of each domain. The arrow in (C) highlights the loss of an α helix in hyb2 relative to the corresponding position in TB4.(E) Comparison of the TB4 and hyb2 domain sequences with the disulphide bond pairings in each indicated. The rearrangement of disulphides in hyb2 compared with TB4 results in the stabilization of a C-terminal β sheet in the hyb2 domain (red bracket).
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fig3: Comparison of Hyb2 and TB4 Domain Structures(A) Superposition of cbEGF9-hyb2-cbEGF10 onto the previously determined structure of fibrillin-1 fragment cbEGF22-TB4_cbEGF23 (Lee et al., 2004) showing the overall similarity of the structures.(B) Superpostion of individual domains of cbEGF9-hyb2-cbEGF10 onto the corresponding regions of cbEGF22-TB4-cbEGF23 indicated that differences in the structures were largely due to small differences seen in the interdomain packing interactions of the different constructs.(C and D) Domain hyb2 (C) has secondary structure elements similar to those seen in TB4 (D) (Lee et al., 2004). A conserved tryptophan (cyan spheres in the 3D models) is involved in forming the hydrophobic core of each domain. The arrow in (C) highlights the loss of an α helix in hyb2 relative to the corresponding position in TB4.(E) Comparison of the TB4 and hyb2 domain sequences with the disulphide bond pairings in each indicated. The rearrangement of disulphides in hyb2 compared with TB4 results in the stabilization of a C-terminal β sheet in the hyb2 domain (red bracket).

Mentions: A superposition of the cbEGF9-hyb2-cbEGF10 structure onto cbEGF22-TB4-cbEGF23 highlighted the high degree of similarity between the structures (Figure 3A). The relatively high root-mean-square deviation (rmsd) value derived from the superposition (2.96 Å) was likely due to small differences in domain packing. Superpositions of the individual domains cbEGF9, hyb2 and cbEGF10 structure onto the corresponding domains in cbEGF22-TB4-cbEGF23 (Figure 3B) showed higher degrees of similarity (rmsd = 0.829, 1.844, and 1.668, respectively), consistent with the conserved nature of the cbEGF fold and similarities between TB and hyb domain sequences.


Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins.

Jensen SA, Iqbal S, Lowe ED, Redfield C, Handford PA - Structure (2009)

Comparison of Hyb2 and TB4 Domain Structures(A) Superposition of cbEGF9-hyb2-cbEGF10 onto the previously determined structure of fibrillin-1 fragment cbEGF22-TB4_cbEGF23 (Lee et al., 2004) showing the overall similarity of the structures.(B) Superpostion of individual domains of cbEGF9-hyb2-cbEGF10 onto the corresponding regions of cbEGF22-TB4-cbEGF23 indicated that differences in the structures were largely due to small differences seen in the interdomain packing interactions of the different constructs.(C and D) Domain hyb2 (C) has secondary structure elements similar to those seen in TB4 (D) (Lee et al., 2004). A conserved tryptophan (cyan spheres in the 3D models) is involved in forming the hydrophobic core of each domain. The arrow in (C) highlights the loss of an α helix in hyb2 relative to the corresponding position in TB4.(E) Comparison of the TB4 and hyb2 domain sequences with the disulphide bond pairings in each indicated. The rearrangement of disulphides in hyb2 compared with TB4 results in the stabilization of a C-terminal β sheet in the hyb2 domain (red bracket).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2724076&req=5

fig3: Comparison of Hyb2 and TB4 Domain Structures(A) Superposition of cbEGF9-hyb2-cbEGF10 onto the previously determined structure of fibrillin-1 fragment cbEGF22-TB4_cbEGF23 (Lee et al., 2004) showing the overall similarity of the structures.(B) Superpostion of individual domains of cbEGF9-hyb2-cbEGF10 onto the corresponding regions of cbEGF22-TB4-cbEGF23 indicated that differences in the structures were largely due to small differences seen in the interdomain packing interactions of the different constructs.(C and D) Domain hyb2 (C) has secondary structure elements similar to those seen in TB4 (D) (Lee et al., 2004). A conserved tryptophan (cyan spheres in the 3D models) is involved in forming the hydrophobic core of each domain. The arrow in (C) highlights the loss of an α helix in hyb2 relative to the corresponding position in TB4.(E) Comparison of the TB4 and hyb2 domain sequences with the disulphide bond pairings in each indicated. The rearrangement of disulphides in hyb2 compared with TB4 results in the stabilization of a C-terminal β sheet in the hyb2 domain (red bracket).
Mentions: A superposition of the cbEGF9-hyb2-cbEGF10 structure onto cbEGF22-TB4-cbEGF23 highlighted the high degree of similarity between the structures (Figure 3A). The relatively high root-mean-square deviation (rmsd) value derived from the superposition (2.96 Å) was likely due to small differences in domain packing. Superpositions of the individual domains cbEGF9, hyb2 and cbEGF10 structure onto the corresponding domains in cbEGF22-TB4-cbEGF23 (Figure 3B) showed higher degrees of similarity (rmsd = 0.829, 1.844, and 1.668, respectively), consistent with the conserved nature of the cbEGF fold and similarities between TB and hyb domain sequences.

Bottom Line: Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 A resolution.Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding.These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, UK.

ABSTRACT
The fibrillins and latent transforming growth factor-beta 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 beta-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 A resolution. The hybrid domain fold is similar, but not identical, to the TB domain fold seen in previous fibrillin-1 and LTBP-1 fragments. Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding. These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

Show MeSH
Related in: MedlinePlus