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Single chain variable fragment against nicastrin inhibits the gamma-secretase activity.

ABSTRACT: Gamma-secretase is a membrane protein complex that catalyzes intramembrane proteolysis of a variety of substrates including the amyloid beta precursor protein of Alzheimer disease. Nicastrin (NCT), a single-pass membrane glycoprotein that harbors a large extracellular domain, is an essential component of the gamma-secretase complex. Here we report that overexpression of a single chain variable fragment (scFv) against NCT as an intrabody suppressed the gamma-secretase activity. Biochemical analyses revealed that the scFv disrupted the proper folding and the appropriate glycosyl maturation of the endogenous NCT, which are required for the stability of the gamma-secretase complex and the intrinsic proteolytic activity, respectively, implicating the dual role of NCT in the gamma-secretase complex. Our results also highlight the importance of the calnexin cycle in the functional maturation of the gamma-secretase complex. The engineered intrabodies may serve as rationally designed, molecular targeting tools for the discovery of novel actions of the membrane proteins.

SUBMITTER: Hayashi I 

PROVIDER: S-EPMC2788834 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Single chain variable fragment against nicastrin inhibits the gamma-secretase activity.

Hayashi Ikuo I   Takatori Sho S   Urano Yasuomi Y   Iwanari Hiroko H   Isoo Noriko N   Osawa Satoko S   Fukuda Maiko A MA   Kodama Tatsuhiko T   Hamakubo Takao T   Li Tong T   Wong Philip C PC   Tomita Taisuke T   Iwatsubo Takeshi T  

The Journal of biological chemistry 20090814 41

Gamma-secretase is a membrane protein complex that catalyzes intramembrane proteolysis of a variety of substrates including the amyloid beta precursor protein of Alzheimer disease. Nicastrin (NCT), a single-pass membrane glycoprotein that harbors a large extracellular domain, is an essential component of the gamma-secretase complex. Here we report that overexpression of a single chain variable fragment (scFv) against NCT as an intrabody suppressed the gamma-secretase activity. Biochemical analys  ...[more]

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