Intramembrane Proteolysis mediated by the gamma -Secretase Complex : Nicastrin Functions as a Substrate Receptor

Show full item record

Title: Intramembrane Proteolysis mediated by the gamma -Secretase Complex : Nicastrin Functions as a Substrate Receptor
Author: Shah, Sanjiv
Abstract: The proteolytic processing of proteins within the lipid bilayer , and release of their membrane tethered biologically active fragments , fundamentally controls a growing list of cell signaling events . The gamma -secretase , one of a small family of independently evolved proteases , performs this enigmatic hydrolysis of a peptide bond within the membrane . Remarkably atypical , gamma -secretase activity : (1 ) requires a complex of proteins that include presenilin , nicastrin , Aph1 , and Pen -2 ; (2 ) catalyzes the intramembrane cleavage of a broad range of substrates , regulating physiology from neurodevelopment to neurodegeneration . The aim of this thesis is to elucidate the mechanism by which the gamma -secretase recognizes its substrates . I provide evidence that nicastrin , in addition to being a critical component of the complex , plays a major function in substrate recognition . The ectodomain of nicastrin binds the new amino terminus that is generated upon the prerequisite 'shedding' of substrates , thereby recruiting substrates into the gamma -secretase complex . The gamma -secretase complex has been traditionally viewed as a hub for signal transduction of substrates such as Notch and APP . The mechanism by which a broad range of substrates may be recognized and subsequently cleaved , as demonstrated in this thesis , supports a mutually inclusive function as a protease that has evolved to simply dispose transmembrane domains thus controlling the repertoire of a class of proteins present in the membrane .
URI: http : / /hdl .handle .net /2152 .5 /410
Date: 2006-08-11

Citation

Intramembrane Proteolysis mediated by the gamma -Secretase Complex : Nicastrin Functions as a Substrate Receptor. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /410 .

Files in this item

Files Size Format View
shahsanjiv.pdf 3.628Mb application/pdf View/Open

This item appears in the following Collection(s)

Show full item record

Search DSpace

Advanced Search

Browse