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The role of structural changes in in...

Gruenke, Jennifer Ann.

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The role of structural changes in influenza hemagglutinin mediated fusion.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The role of structural changes in influenza hemagglutinin mediated fusion./
Author:	Gruenke, Jennifer Ann.
Description:	135 p.
Notes:	Adviser: Judith M. White.
Contained By:	Dissertation Abstracts International62-10B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3030677
ISBN:	0493429581

The role of structural changes in influenza hemagglutinin mediated fusion.
Gruenke, Jennifer Ann.

The role of structural changes in influenza hemagglutinin mediated fusion. - 135 p.

Adviser: Judith M. White.

Thesis (Ph.D.)--University of Virginia, 2002.

Influenza hemagglutinin (HA) undergoes a conformational change in the acidic environment of the endosome, promoting fusion of the viral and endosomal membranes, and allowing entry of the viral genome into the cytoplasm. This work describes two major projects: testing a model for HA-mediated fusion, and analyzing compounds that inhibit HA-mediated fusion. The first phase of this work (Chapter 2) describes experiments that test the “spring-loaded” conformational change of HA, which results in the formation of a coiled-coil that is the core of a six-stranded bundle. Residues in “a” and “d” positions of the “B” loop region were singly or doubly substituted with proline to disrupt formation of a complete coiled-coil. Of nine single proline substitutions, two caused reduced fusion, while the others caused normal fusion. Of three double proline substitutions, none mediated any fusion, either lipid or content mixing. One double proline mutant (F63P/F70P) was further analyzed to determine at what stage of fusion this mutant is impaired, and to determine if it forms a complete coiled-coil. F63P/F70P bound target membranes independently of receptor binding. F63P/F70P does not form a complete coiled-coil, but one of the single mutants that promotes fusion does form a complete coiled-coil. Together, these results support the hypothesis that the spring-loaded conformational change is required for fusion. They also suggest a role for the spring-loaded conformational change beyond presentation of the fusion peptide to the target membrane.

ISBN: 0493429581Subjects--Topical Terms:

1017686
Biology, Cell.

The role of structural changes in influenza hemagglutinin mediated fusion.
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020 $a 0493429581
035 $a (UnM)AAI3030677
035 $a AAI3030677
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100 1 $a Gruenke, Jennifer Ann. $3 1262735
245 1 0 $a The role of structural changes in influenza hemagglutinin mediated fusion.
300 $a 135 p.
500 $a Adviser: Judith M. White.
500 $a Source: Dissertation Abstracts International, Volume: 62-10, Section: B, page: 4316.
502 $a Thesis (Ph.D.)--University of Virginia, 2002.
520 $a Influenza hemagglutinin (HA) undergoes a conformational change in the acidic environment of the endosome, promoting fusion of the viral and endosomal membranes, and allowing entry of the viral genome into the cytoplasm. This work describes two major projects: testing a model for HA-mediated fusion, and analyzing compounds that inhibit HA-mediated fusion. The first phase of this work (Chapter 2) describes experiments that test the “spring-loaded” conformational change of HA, which results in the formation of a coiled-coil that is the core of a six-stranded bundle. Residues in “a” and “d” positions of the “B” loop region were singly or doubly substituted with proline to disrupt formation of a complete coiled-coil. Of nine single proline substitutions, two caused reduced fusion, while the others caused normal fusion. Of three double proline substitutions, none mediated any fusion, either lipid or content mixing. One double proline mutant (F63P/F70P) was further analyzed to determine at what stage of fusion this mutant is impaired, and to determine if it forms a complete coiled-coil. F63P/F70P bound target membranes independently of receptor binding. F63P/F70P does not form a complete coiled-coil, but one of the single mutants that promotes fusion does form a complete coiled-coil. Together, these results support the hypothesis that the spring-loaded conformational change is required for fusion. They also suggest a role for the spring-loaded conformational change beyond presentation of the fusion peptide to the target membrane.
520 $a The second phase of this work (Chapter 3) describes experiments that analyze the mechanism of action of compounds that inhibit or promote the HA conformational change. The compound TBHQ, which inhibits fusion peptide exposure, reversibly inhibited lipid mixing, but not head group separation. This suggests that head group separation alone does not lead to either fusion or HA inactivation. The compound C22 potentiated head group separation, even after reneutralization of HA, indicating that it may bind to a conformational intermediate. Other projects described in this work include attempts to obtain the crystal structure of a compound bound to BHA (Chapter 4), and testing of compounds predicted by the program DOCK to bind to BHA (Chapter 3).
590 $a School code: 0246.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Microbiology. $3 1017734
690 $a 0379
690 $a 0410
710 2 0 $a University of Virginia. $3 645578
773 0 $t Dissertation Abstracts International $g 62-10B.
790 $a 0246
790 1 0 $a White, Judith M., $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3030677