Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1.
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.
Hayashi
Mirian A F
MA
Center for Applied Toxinology, Laboratories of Immunogenetics and Immunochemistry, Butantan Institute, and Laboratory of Neurosciences, Universidade Cidade de São Paulo, SP 05503-900, São Paulo, Brazil.
Portaro
Fernanda C V
FC
Bastos
Marta F
MF
Guerreiro
Juliano R
JR
Oliveira
Vitor
V
Gorrão
Silvia S
SS
Tambourgi
Denise V
DV
Sant'Anna
Osvaldo A
OA
Whiting
Paul J
PJ
Camargo
L Miguel
LM
Konno
Katsuhiro
K
Brandon
Nicholas J
NJ
Camargo
Antonio C M
AC
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003001:Cloning, Molecular; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051381:Rats; D012559:Schizophrenia / Q000209:etiology
D002352:Carrier Proteins; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; C498795:Disc1 protein, rat; C421108:NDEL1 protein, human; D009419:Nerve Tissue Proteins; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase
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