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Investigating Protein Sequence-structure-dynamics Relationships with Bio3D-web
Published on: July 16, 2017
Structural analysis of the N-terminal fragment of the antiangiogenic protein endostatin: a molecular dynamics study
Pedro Henrique Monteiro Torres1, Gabriel Limaverde Soares Costa Sousa, Pedro Geraldo Pascutti
1Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, 21941-902, Rio de Janeiro, RJ, Brazil. monteirotorres@biof.ufrj.br
Abstract:
Endostatin is a potent antiangiogenic protein derived from the noncollagenous domain 1 (NC1) of collagen XVIII. The mechanism by which endostatin exerts its antiangiogenic effect is still incompletely understood. It has been shown that the 27 amino acid N-terminal fragment of murine endostatin has antitumor, antimigration, and antipermeability activities comparable to the full soluble protein. To understand how this peptide can exert such elaborate function, we performed structural analysis using molecular dynamics to evaluate the behavior of this fragment in aqueous environment. Here, we show that the N-terminal peptide of murine endostatin is able to assume a well-defined structure, folding into a zinc-dependent β-hairpin conformation. Analyzing the folding mechanism, we were able to understand why the N-terminal peptide of human endostatin with the same length failed to acquire a stable conformation. Conversely, we were able to predict the successful folding of the R4Q mutant and of a shorter form of the human peptide with 25 residues. Finally, we show that the β-hairpin conformation assumed by the zinc-bound peptide of murine endostatin has a high structural similarity with fragments of another family of angiogenesis inhibitors: the integrin-binding portion of the NC1 domain of collagen IV. Indeed, our docking simulations show that arresten, canstatin, and the endostatin peptide bind to the same spot of αVβ3 integrin, suggesting similar interactions via a common binding site on this receptor.
Insights
The N-terminal fragment of endostatin (a collagen XVIII protein) forms a stable, zinc-dependent β-hairpin structure, explaining its antiangiogenic activity. This structure is similar to other angiogenesis inhibitors targeting the αVβ3 integrin receptor.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Endostatin, derived from collagen XVIII, is a potent antiangiogenic protein.
- Its mechanism of action is not fully understood, particularly for its N-terminal fragment.
- The 27 amino acid N-terminal fragment of murine endostatin exhibits significant antitumor and antiangiogenic properties.
Purpose of the Study:
- To elucidate the structural basis of the N-terminal endostatin peptide's antiangiogenic function.
- To understand the folding mechanism and stability of the murine endostatin N-terminal fragment.
- To compare the structural behavior of murine and human endostatin peptides and predict functional variants.
Main Methods:
- Molecular dynamics simulations to analyze peptide behavior in aqueous environments.
- Structural analysis to determine the conformation of the N-terminal peptide.
- Docking simulations to investigate receptor binding interactions.
Main Results:
- The N-terminal peptide of murine endostatin folds into a stable, zinc-dependent β-hairpin conformation.
- The folding mechanism explains the instability of the equivalent human peptide and predicts successful folding for mutants and shorter human forms.
- The β-hairpin structure shares similarities with collagen IV NC1 domain fragments, suggesting a common binding site on the αVβ3 integrin receptor for endostatin, arresten, and canstatin.
Conclusions:
- The zinc-bound β-hairpin conformation is crucial for the antiangiogenic activity of the endostatin N-terminal peptide.
- Structural insights reveal potential for designing new angiogenesis inhibitors based on the endostatin scaffold.
- Shared binding interactions with αVβ3 integrin suggest a common mechanism of action among different angiogenesis inhibitors.