Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite

0489934 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
Hánová, Iva - Brynda, Jiří - Houštecká, Radka - Alam, N. - Sojka, Daniel - Kopáček, Petr - Marešová, Lucie - Vondrášek, Jiří - Horn, Martin - Schueler-Furman, O. - Mareš, Michael
Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite.
Cell Chemical Biology. Roč. 25, č. 3 (2018), s. 318-329. ISSN 2451-9448. E-ISSN 2451-9448
Grant CEP: GA ČR GA15-18929S; GA ČR GA13-11043S; GA MŠMT LO1302; GA ČR GA14-33693S
Institucionální podpora: RVO:61388963 ; RVO:60077344
Klíčová slova: cathepsin D * activation intermediate * crystal structure
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.762, rok: 2018
https://www.sciencedirect.com/science/article/pii/S2451945618300011?via%3Dihub

Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide. This fragment functions as an effective natural inhibitor of mature IrCD1 that operates in a pH-dependent manner through a unique allosteric inhibition mechanism. The study uncovers the propeptide-binding exosite as a target for the regulation of pepsin-family aspartic peptidases and defines the structural requirements for exosite inhibition.
Trvalý link: http://hdl.handle.net/11104/0284232