Solution structure and biochemistry of an intramembrane aspartyl protease (IAP)

Naing, Swe-Htet

Title:

Solution structure and biochemistry of an intramembrane aspartyl protease (IAP)

dc.contributor.advisor	Oyelere, Adegboyega K.
dc.contributor.author	Naing, Swe-Htet
dc.contributor.committeeMember	Lieberman, Raquel
dc.contributor.committeeMember	Williams, Loren
dc.contributor.committeeMember	Peralta-Yahya, Pamela
dc.contributor.committeeMember	Wartell, Roger
dc.contributor.department	Chemistry and Biochemistry
dc.date.accessioned	2018-05-31T18:13:29Z
dc.date.available	2018-05-31T18:13:29Z
dc.date.created	2018-05
dc.date.issued	2018-03-08
dc.date.submitted	May 2018
dc.date.updated	2018-05-31T18:13:29Z
dc.description.abstract	Intramembrane proteases (IPs) play important roles in numerous biochemical processes in all kingdoms of life, including cell differentiation, development and metabolism. IPs are attractive targets for therapeutics development and have been implicated in the pathogenesis of human diseases, such as Alzheimer’s disease, Hepatitis C, malaria and a variety of cancers. Despite their broad medical and biological relevance, structural and mechanistic details of IPs have remained largely obscure. A continuous FRET peptide assay, which is fast, robust, and high throughput, and can be applied to screen multiple conditions simultaneously, is developed. Catalytic parameters and cleavage sites of a fortuitous substrate, angiotensinogen, and Alzheimer disease linked C100 substrate, in detergent and bicelle conditions highlighted the importance of substrate-membrane, substrate-enzyme and enzyme-membrane interactions. Through structure-function analysis of a model IAP from the archaeon Methanoculleus marisnigri JR1 (mIAP), the catalytic motifs and substrate gating motifs were found to influence the catalytic efficiency but not the processivity and specificity of cleavages. Both positional and chemical variables were found to control the substrate specificity of mIAP. Small-angle neutron scattering (SANS) study showed that mIAP is a compact monomer in solution. Future direction of study on expanding substrate repertoire, evaluating effects of Alzheimer disease mutations, and structural characterization of substrate-enzyme-membrane complexes are discussed.
dc.description.degree	Ph.D.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/59863
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	Intramembrane proteolysis
dc.subject	Membrane enzyme
dc.subject	Enzyme kinetics
dc.subject	Substrate specificity
dc.subject	Mass spectrometry
dc.subject	Presenilin
dc.subject	Amyloid precursor protein
dc.subject	Alzheimer’s disease
dc.subject	Neurodegenerative disease
dc.title	Solution structure and biochemistry of an intramembrane aspartyl protease (IAP)
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.advisor	Oyelere, Adegboyega K.
local.contributor.corporatename	School of Chemistry and Biochemistry
local.contributor.corporatename	College of Sciences
relation.isAdvisorOfPublication	559ad46f-fbf0-4834-aed9-4c606a8e0790
relation.isOrgUnitOfPublication	f1725b93-3ab8-4c47-a4c3-3596c03d6f1e
relation.isOrgUnitOfPublication	85042be6-2d68-4e07-b384-e1f908fae48a
thesis.degree.level	Doctoral