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Structure-Function Analysis of a Model for Alpha-Synuclein Function.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Structure-Function Analysis of a Model for Alpha-Synuclein Function./
作者:	Das, Tapojyoti.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	183 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28545810
ISBN:	9798538121687

Structure-Function Analysis of a Model for Alpha-Synuclein Function.
Das, Tapojyoti.

Structure-Function Analysis of a Model for Alpha-Synuclein Function. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 183 p.

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2021.

This item must not be sold to any third party vendors.

Alpha-synuclein (aSyn), the principal protein forming toxic intraneuronal aggregates in Parkinson's disease, has a poorly defined physiological function related to regulation of neurotransmitter release. The pathology of Parkinson's disease is likely in part mediated by the loss of normal physiological function of this protein. Hence, understanding the physiological structure-function relationship will help understand the disease pathology and assist novel therapeutic efforts. Structurally, the N-terminal ~100-residue membrane-binding domain of aSyn interconverts between an extended helix and a broken helix conformation, with unknown functional significance. In this study, we draw a correlation between aSyn structure and function using a combination of structural studies using NMR and other biophysical methods, and functional assay of Ca2+-triggered exocytosis in mammalian cells. Expressing alpha-synuclein at two different concentrations, both within the reported physiological range, we show that wild-type aSyn acts as an inhibitor of Ca2+-triggered exocytosis at low expression level, which is correlated to its ability to form a broken helix conformation on binding to detergent micelles in vitro. In addition, at a high expression level we report an exocytosis potentiation function caused by redistribution of vesicles from the perinuclear region to plasma membrane-proximal zone, which is correlated to its ability to bind artificial lipid vesicles at an extended helical conformation. Next, we explore the contribution of the flexibility of the linker region between two helices to its structure and function, and find that a critical balance of rigidity and flexibility of the linker region is important for its dual functional role. Furthermore, we find that membrane-binding kinetics could also play a possible role in either function. These two opposing functions are apparently balanced in normal physiology but may become unbalanced in the context of disease.

ISBN: 9798538121687Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Alpha-synuclein

Structure-Function Analysis of a Model for Alpha-Synuclein Function.
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520 $a Alpha-synuclein (aSyn), the principal protein forming toxic intraneuronal aggregates in Parkinson's disease, has a poorly defined physiological function related to regulation of neurotransmitter release. The pathology of Parkinson's disease is likely in part mediated by the loss of normal physiological function of this protein. Hence, understanding the physiological structure-function relationship will help understand the disease pathology and assist novel therapeutic efforts. Structurally, the N-terminal ~100-residue membrane-binding domain of aSyn interconverts between an extended helix and a broken helix conformation, with unknown functional significance. In this study, we draw a correlation between aSyn structure and function using a combination of structural studies using NMR and other biophysical methods, and functional assay of Ca2+-triggered exocytosis in mammalian cells. Expressing alpha-synuclein at two different concentrations, both within the reported physiological range, we show that wild-type aSyn acts as an inhibitor of Ca2+-triggered exocytosis at low expression level, which is correlated to its ability to form a broken helix conformation on binding to detergent micelles in vitro. In addition, at a high expression level we report an exocytosis potentiation function caused by redistribution of vesicles from the perinuclear region to plasma membrane-proximal zone, which is correlated to its ability to bind artificial lipid vesicles at an extended helical conformation. Next, we explore the contribution of the flexibility of the linker region between two helices to its structure and function, and find that a critical balance of rigidity and flexibility of the linker region is important for its dual functional role. Furthermore, we find that membrane-binding kinetics could also play a possible role in either function. These two opposing functions are apparently balanced in normal physiology but may become unbalanced in the context of disease.
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