Your browser doesn't support javascript.
loading
Maturation of the malarial phosphatidylserine decarboxylase is mediated by high affinity binding to anionic phospholipids.
Choi, Jae-Yeon; Lopes, Lauren; Ben Mamoun, Choukri; Voelker, Dennis R.
Afiliación
  • Choi JY; Basic Science Section, Department of Medicine, National Jewish Health, Denver, Colorado, USA; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
  • Lopes L; Basic Science Section, Department of Medicine, National Jewish Health, Denver, Colorado, USA.
  • Ben Mamoun C; Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
  • Voelker DR; Basic Science Section, Department of Medicine, National Jewish Health, Denver, Colorado, USA. Electronic address: voelkerd@njhealth.org.
J Biol Chem ; 299(5): 104659, 2023 05.
Article en En | MEDLINE | ID: mdl-36997087
Decarboxylation of phosphatidylserine (PS) to form phosphatidylethanolamine by PS decarboxylases (PSDs) is an essential process in most eukaryotes. Processing of a malarial PSD proenzyme into its active alpha and beta subunits is by an autoendoproteolytic mechanism regulated by anionic phospholipids, with PS serving as an activator and phosphatidylglycerol (PG), phosphatidylinositol, and phosphatidic acid acting as inhibitors. The biophysical mechanism underlying this regulation remains unknown. We used solid phase lipid binding, liposome-binding assays, and surface plasmon resonance to examine the binding specificity of a processing-deficient Plasmodium PSD (PkPSDS308A) mutant enzyme and demonstrated that the PSD proenzyme binds strongly to PS and PG but not to phosphatidylethanolamine and phosphatidylcholine. The equilibrium dissociation constants (Kd) of PkPSD with PS and PG were 80.4 nM and 66.4 nM, respectively. The interaction of PSD with PS is inhibited by calcium, suggesting that the binding mechanism involves ionic interactions. In vitro processing of WT PkPSD proenzyme was also inhibited by calcium, consistent with the conclusion that PS binding to PkPSD through ionic interactions is required for the proenzyme processing. Peptide mapping identified polybasic amino acid motifs in the proenzyme responsible for binding to PS. Altogether, the data demonstrate that malarial PSD maturation is regulated through a strong physical association between PkPSD proenzyme and anionic lipids. Inhibition of the specific interaction between the proenzyme and the lipids can provide a novel mechanism to disrupt PSD enzyme activity, which has been suggested as a target for antimicrobials, and anticancer therapies.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfolípidos / Plasmodium / Carboxiliasas / Malaria Tipo de estudio: Prognostic_studies Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfolípidos / Plasmodium / Carboxiliasas / Malaria Tipo de estudio: Prognostic_studies Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos