Interaction of the brain-specific protein p42IP4/centaurin- α1 with the peptidase nardilysin is regulated by the cognate ligands of p42IP4, PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4, with stereospecificity

Rolf Stricker, K. Martin Chow, Daniela Walther, Theodor Hanck, Louis B. Hersh, Georg Reiser

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The brain-specific protein p42IP4, also called centaurin-α1, specifically binds phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]. Here, we investigate the interaction of p42 IP4/ centaurin-α1 with nardilysin (NRDc), a member of the M16 family of zinc metalloendopeptidases. Members of this peptidase family exhibit enzymatic activity and also act as receptors for other proteins. We found that p42IP4/centaurin-α1 binds specifically to NRDc from rat brain. We further detected that centaurin-α2, a protein that is highly homologuous to p42IP4/centaurin-α1 and expressed ubiquitously, also binds to NRDc. In vivo interaction was demonstrated by co- immunoprecipitation of p42IP4/centaurin-α1 with NRDc from rat brain. The acidic domain of NRDc (NRDc-AD), which does not participate in catalysis, is sufficient for the protein interaction with p42IP4. Interestingly, preincubation of p42IP4 with its cognate ligands D-Ins(1,3,4,5)P4 and the lipid diC8Pt-dIns(3,4,5)P3 negatively modulates the interaction between the two proteins. D-Ins(1,3,4,5)P4 and diC8PtdIns(3,4,5)P3 suppress the interaction with virtually identical concentration dependencies. This inhibition is highly ligand specific. The enantiomer L-Ins(1,3,4,5)P4 is not effective. Similarly, the phosphoinositides diC8PtdIns(3,4)P2, diC8PtdIns(3,5)P2 and diC8PtdIns(4,5)P2 all have no influence on the interaction. Further experiments revealed that endogenous p42IP4 from rat brain binds to glutathione-S-transferase (GST)-NRDc-AD. The proteins dissociate from each other when incubated with D-Ins(1,3,4,5)P4, but not with inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. In summary, we demonstrate that p42IP4 binds to NRDc via the NRDc-AD, and that this interaction is controlled by the cognate cellular ligands of p42IP4/centaurin-α1. Thus, specific ligands of p42IP4 can modulate the recruitment of proteins, which are docked to p42IP4, to specific cellular compartments.

Original languageEnglish
Pages (from-to)343-354
Number of pages12
JournalJournal of Neurochemistry
Volume98
Issue number2
DOIs
StatePublished - Jul 2006

Keywords

  • Centaurins
  • Inositolphosphate
  • PH domain
  • Phosphoinositides
  • Protein-protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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