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Document Type:Latin Dissertation
Language of Document:English
Record Number:53780
Doc. No:TL23734
Call number:‭3510170‬
Main Entry:Emanuel Perugia
Title & Author:Towards an understanding of the serum amyloid A (SAA) protein amyloid formationEmanuel Perugia
College:The Weizmann Institute of Science (Israel)
Date:2009
Degree:Ph.D.
student score:2009
Page No:91
Abstract:Serum amyloid a (SAA) is a family of small proteins 12 kDa (104-114 aa) associated in serum with High Density Lipoproteins (HDL 3), highly conserved in vertebrates. During states of inflammation its in-vivo concentration, often, rises as much as 1000-fold above normal level (up to 1mg/ml) suggesting that it might play a beneficial short-term role in host defense and tissue injury. Although the primary physiological role of the SAA proteins remains obscure, various effects and proposed functions have been reported. These include: host-defense, modulation of the inflammatory response via anti- and pro-inflammatory activities and involvement in cholesterol transport and metabolism. Continuous high concentration of SAA throughout longer periods of time, induced by several chronic conditions, such as autoimmune and chronic diseases is causing disorders such as atherosclerosis and Amyloidosis A. The AA (amyloidosis A) is one of the most common forms of systemic amyloidosis; it is generated from the pathological aggregation and fibril formation of the (SAA) protein that invades the extra-cellular spaces of organs, destroying normal tissue structure and function. The aim of the present research was to investigate the mechanism behind SAA pathological aggregation and amyloid formation. Specific aims were: 1) Identification of recognition motif(s) inside the hSAA1 protein relevant for amyloid formation. 2) Identification of specific residues within the hSAA1 protein significant for amyloid formation through chemical point mutation. 3) Cloning, expression and purification of the hSAA1 protein and its mutants for structural studies. In the following we describe our major findings that can be summarized in: 1) the reduction of the known amyloidogenic N-terminal domain (SAA 1→12: SFFSFLGEAFD) to the penta-peptide SAA 2→6 (SFFSF); 2) Assessment, through deletions and chemical point mutations of a destabilizing effect of the N-terminal arginine on amyloid formation in SAA derived peptides up to 8 amino-acids in length; 3) Discovery of a second and a third previously unknown amyloidogenic domains encompassing respectively residues 50→59 and 63→72, those domains have been unified in larger peptide SAA 47→76 fully maintaining amyloidogenicity; 4) The native hSAA1 and seven mutants, generated by site-directed mutagenesis have been successfully cloned and expressed. The SAA protein in light of our findings appears to have a much greater amyloidogenic potential than previously thought.
Subject:Pure sciences; Cholesterol transport; High density lipoproteins; Inflammatory response; Protein amyloid formation; Serum amyloid A; Biochemistry; Organic chemistry; 0490:Organic chemistry; 0487:Biochemistry
Added Entry:M. Fridkin
Added Entry:The Weizmann Institute of Science (Israel)