Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.
PubMed
29396291
DOI
10.1016/j.chembiol.2018.01.001
PII: S2451-9456(18)30001-1
Knihovny.cz E-zdroje
- Klíčová slova
- allosteric inhibitor, aspartic peptidase, crystal structure, exosite, proteolysis,
- MeSH
- aktivace enzymů MeSH
- alosterická regulace MeSH
- katalytická doména MeSH
- kathepsin D chemie metabolismus MeSH
- kinetika MeSH
- klíšťata enzymologie MeSH
- koncentrace vodíkových iontů MeSH
- krystalografie rentgenová MeSH
- ligandy MeSH
- peptidy chemie metabolismus MeSH
- prekurzory enzymů chemie metabolismus MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- kathepsin D MeSH
- ligandy MeSH
- peptidy MeSH
- prekurzory enzymů MeSH
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.
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