Elastic fibers are an important component of the extracellular matrix, providing elasticity and resilience to tissues that require the ability to deform repetitively and reversibly. Among the elastin-derived peptides, the Val-Gly-Val-Ala-Pro-Gly (VGVAPG) hexapeptide is known for its chemotactic activity and metalloproteinases upregulation properties. As other elastin-derived peptides, having homologous similar sequences, do not exhibit any biological activity, the following question arises: Does the peptide-receptor interaction need a specific active conformation? Previous experimental studies including NMR and CD spectroscopies did not clearly identify the conformations adopted by the VGVAPG peptide in solution. However, structural predictions made on VGVAPG and related XGXXPG peptides suggested a folded beta-turn conformation. So we undertook a theoretical and experimental study of the VGVAPG peptide. The work presented here, which gives an overall structural description of VGVAPG behavior in water, also provides an additional insight into its structure-activity relationship. Both theoretical and experimental results suggest the existence of an ensemble of rather extended and folded conformations in solution. All the folded structures obtained exhibit a type VIII beta-turn spanning the GVAP sequence. In the lack of any structural information concerning the elastin receptor, these results suggest that such a conformation could be relevant for the peptide-receptor interaction and thus for biological activity.

The degradation of elastin, the insoluble biopolymer of tropoelastin, can lead to the production of small peptides. These elastin-derived peptides (EDPs) are playing a key role in cellular behavior within the extracellular matrix, showing a great variety of biological effects such as chemotaxis, stimulation of cell proliferation, ion flux modifications, vasorelaxation, and inflammatory enzymes secretion. It has also been demonstrated recently that EDPs containing the GXXPG motif could induce pro-MMP1 and pro-MMP3 upregulation. Elastolysis could then cause collagen degradation and play an important role in the aging process. Many experimental studies have been devoted to EDPs, but their structure/activity relationships are not well elucidated yet. However, the assumption that their active conformation is a type VIII beta-turn on GXXP was highly suggested on the basis of predictive statistical calculations. Investigation of the EDPs three-dimensional (3D) structure would provide useful information for drug-design strategies to propose specific inhibitors. The work presented here reports theoretical results obtained from molecular dynamics simulations performed over 128 human EDPs containing the GXXP motif. We show that all the peptides, for which the central residues are not glycines, adopt a canonical (or very close to) type VIII beta-turn structure on the GXXP sequence. Amino acids surrounding this motif are also important for the structural behavior. Any residue located before the GXXP motif (XGXXP) increases the beta-turn stabilization, whereas the residue located after GXXP (GXXPX) has no significant structural effect. Moreover, we show their biological activity can be correlated with their ability to exhibit a type VIII beta-turn conformation.

Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.

Elastin-derived peptides (EDPs) have been intensively studied in view of their widely diverse biological activities. These are triggered both in normal and tumor cells, through peptide anchoring at the surface of the elastin-binding protein (EBP), a subunit of the elastin/laminin receptor. In this study, we investigated both the structure of the Sgal peptide, representing the elastin-binding domain of EBP, and its interaction with EDPs, through a combination of experimental and theoretical methods. Although the conformation of the Sgal peptide is highly flexible, we detected a type I beta-turn at the QDEA sequence. This represents the best structured motif in the entire Sgal peptide, which might therefore contribute to its binding activity. We further propose a novel three-dimensional model for the interaction between the Sgal peptide and EDPs; folding of the EDPs at the GXXP motif, in a conformation close to a type VIII beta-turn, provides the efficient contact of the protein with the Q residue of the Sgal peptide. This residue is exposed to the peptide surface, because of the beta-turn structure of the QDEA residues in the peptide sequence. We further show that this complex is stabilized by three hydrogen bonds involving EDPs backbone atoms.