{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/410"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/410","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Intramembrane Proteolysis Mediated by the gamma-Secretase Complex : Nicastrin Functions as a Substrate Receptor","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Shah, Sanjiv"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Yu, Gang"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07-12T17:58:15Z","date_published":"2010-07-12T17:58:15Z","updated_at":"2026-07-24T05:52:20Z","subjects":["Membrane Proteins","Hydrolysis","Proteolysis"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["182523067"],"render_values":[{"text":"182523067","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/410","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Yu, Gang"]},{"key":"dc:creator","label":"Author","values":["Shah, Sanjiv"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T17:58:15Z","2006-08-11"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Membrane Proteins","Hydrolysis","Proteolysis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/410","182523067"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["Intramembrane Proteolysis Mediated by the gamma-Secretase Complex : Nicastrin Functions as a Substrate Receptor"]}]}],"canonical_facts":{"dc:contributor":["Yu, Gang"],"dc:creator":["Shah, Sanjiv"],"dc:date":["2010-07-12T17:58:15Z","2006-08-11"],"dc:description":["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."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/410","182523067"],"dc:language":["en"],"dc:subject":["Membrane Proteins","Hydrolysis","Proteolysis"],"dc:title":["Intramembrane Proteolysis Mediated by the gamma-Secretase Complex : Nicastrin Functions as a Substrate Receptor"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:20Z"}