GASP-1 and GASP-2, two closely structurally related proteins with a functional duality in antitrypsin inhibition specificity: a mechanistic point of view.

Alexis Parenté, Florent Di Meo, Eric Lapeyronie, Montasir Al Mansi, Didier Delourme, Patrick Pélissier, Laure Brémaud, Patrick Trouillas, Véronique Blanquet

The FEBS journal 2020 Mar

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While GASP-1 and GASP-2 proteins are known to regulate myogenesis by inhibiting myostatin, their structural organization suggests a putative role as multivalent protease inhibitors controlling different protease activities. In this study, we show the noncompetitive and competitive antitrypsin activities of the full-length GASP-1 and GASP-2 proteins, respectively, by using a bacterial system production and in vitro enzymatic experiments. The role of the second Kunitz domain in this functional duality is described by assessing the antitrypsin activity of GASP-1/2 chimeric proteins. Molecular dynamics simulations support the experimental data to rationalize differences in binding modes between trypsin and the GASP-1 and GASP-2 second Kunitz domains. A new inhibition mechanism was evidenced for the second Kunitz domain of GASP-2, in which the conventional cationic residue of trypsin inhibitors was substituted by the strongly interacting glutamine residue. © 2019 Federation of European Biochemical Societies.

Citation

Alexis Parenté, Florent Di Meo, Eric Lapeyronie, Montasir Al Mansi, Didier Delourme, Patrick Pélissier, Laure Brémaud, Patrick Trouillas, Véronique Blanquet. GASP-1 and GASP-2, two closely structurally related proteins with a functional duality in antitrypsin inhibition specificity: a mechanistic point of view. The FEBS journal. 2020 Mar;287(5):909-924