TY - JOUR
T1 - 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
AU - Stricker, Rolf
AU - Chow, K. Martin
AU - Walther, Daniela
AU - Hanck, Theodor
AU - Hersh, Louis B.
AU - Reiser, Georg
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
KW - Centaurins
KW - Inositolphosphate
KW - PH domain
KW - Phosphoinositides
KW - Protein-protein interaction
UR - http://www.scopus.com/inward/record.url?scp=33746533742&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746533742&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2006.03869.x
DO - 10.1111/j.1471-4159.2006.03869.x
M3 - Article
C2 - 16805830
AN - SCOPUS:33746533742
SN - 0022-3042
VL - 98
SP - 343
EP - 354
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 2
ER -