Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1.

Abstract

Recently, nuclear distribution element-like (NUDEL) has been implicated to play a role in lissencephaly and schizophrenia through interactions with the lissencephaly gene 1 (Lis1) and disrupted-in-schizophrenia 1 (DISC1) products, respectively. Interestingly, NUDEL is the same protein as endooligopeptidase A (EOPA), a thiol-activated peptidase involved in conversion and inactivation of a number of bioactive peptides. In this study, we have cloned EOPA from the human brain and have confirmed that it is equivalent to NUDEL, leading us to suggest a single name, NUDEL-oligopeptidase. In the brain, the monomeric form of NUDEL-oligopeptidase is responsible for the peptidase activity whose catalytic mechanism is likely to involve a reactive cysteine, because mutation of Cys-273 fully abolished NUDEL-oligopeptidase activity without disrupting the protein's secondary structure. Cys-273 is very close to the DISC1-binding site on NUDEL-oligopeptidase. Intriguingly, DISC1 inhibits NUDEL-oligopeptidase activity in a competitive fashion. We suggest that the activity of NUDEL-oligopeptidase is under tight regulation through protein-protein interactions and that disruption of these interactions, as postulated in a Scottish DISC1 translocation schizophrenia cohort, may lead to aberrant regulation of NUDEL-oligopeptidase, perhaps providing a substrate for the pathology of schizophrenia.

• Authors: Mirian A F Hayashi, Fernanda C V Portaro, Marta F Bastos, Juliano R Guerreiro, Vitor Oliveira, Silvia S Gorrão, Denise V Tambourgi, Osvaldo A Sant'Anna, Paul J Whiting, L Miguel Camargo, Katsuhiro Konno, Nicholas J Brandon, Antonio C M Camargo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 10 Pg. 3828-33 (Mar 08 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15728732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• DISC1 protein, human
• Disc1 protein, mouse
• Disc1 protein, rat
• NDEL1 protein, human
• Nerve Tissue Proteins
• Metalloendopeptidases
• thimet oligopeptidase

Topics

• Animals
• Base Sequence
• Brain (enzymology)
• Carrier Proteins (antagonists & inhibitors, metabolism)
• Cloning, Molecular
• Humans
• Male
• Metalloendopeptidases (antagonists & inhibitors, metabolism)
• Mice
• Molecular Sequence Data
• Nerve Tissue Proteins (physiology)
• Rats
• Schizophrenia (etiology)