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Modular HIV-1 Capsid Assemblies for ...

Summers, Brady J.

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Modular HIV-1 Capsid Assemblies for Investigating Diverse Host Recognition Mechanisms.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Modular HIV-1 Capsid Assemblies for Investigating Diverse Host Recognition Mechanisms./
作者:	Summers, Brady J.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	168 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13850213
ISBN:	9780438973459

Modular HIV-1 Capsid Assemblies for Investigating Diverse Host Recognition Mechanisms.
Summers, Brady J.

Modular HIV-1 Capsid Assemblies for Investigating Diverse Host Recognition Mechanisms. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 168 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item is not available from ProQuest Dissertations & Theses.

The human immunodeficiency virus-1 (HIV-1) capsid is an ordered protein shell built from a repeating array of the viral CA protein. The assembled capsid houses and protects the viral genome during early stages of infection. Once inside an infected cell, it is an expansive protein-docking platform whose finely-tuned structural integrity is critical for viral infection. Numerous host factors, both beneficial and harmful to the virus, recognize and directly bind specific capsid surfaces. Unfortunately, our mechanistic understanding of host-capsid interactions is well behind that of our knowledge of apo capsid structure. This is because many capsid binding factors only recognize high-order capsid lattice patterns and do not show appreciable affinity for soluble capsid building blocks, such as CA dimers and hexamers. Without appropriate CA-binding partners, host factor-CA complexes cannot be formed in solution, and the vast array of solution-based biochemical and structural biology techniques cannot be applied. To overcome these limitations, I developed novel techniques to trap and stabilize CA oligomers in lattice-like fragments that are intermediates between unassembled and fully assembled capsid. These engineered lattice assemblies range in size from 50 kDa to 1 MDa (or 2-42 CA molecules) and exhibit every unique capsid lattice interface found in infectious virions. Many of the assemblies bridge the hexamer-hexamer and hexamer-pentamer surfaces formed by the CA C-terminal domains that have been previously impossible to capture. These lattice-intermediates enable analysis of elusive capsid-host factor binding events in solution-avoiding the pitfalls associated with capsid tubes and cones. I have used these assemblies to better define the unique capsid-binding modes of several well-studied, but poorly understood, restriction factors (TRIM5a, TRIMCyp, and MxB) and a recently discovered viral cofactor (FEZ1). Each of these factors demonstrated a unique capsid lattice-sensing ability that could only be defined with our novel CA assemblies. This work significantly expands our understanding of the diverse array of capsid-sensing motifs and targetable capsid surfaces. Besides mechanistic investigations, the advanced toolkit we have created will be valuable for searching for additional capsidbinding factors or designing specific capsid-targeting therapeutics to inhibit HIV-1 infectivity.

ISBN: 9780438973459Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Capsid

Modular HIV-1 Capsid Assemblies for Investigating Diverse Host Recognition Mechanisms.
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520 $a The human immunodeficiency virus-1 (HIV-1) capsid is an ordered protein shell built from a repeating array of the viral CA protein. The assembled capsid houses and protects the viral genome during early stages of infection. Once inside an infected cell, it is an expansive protein-docking platform whose finely-tuned structural integrity is critical for viral infection. Numerous host factors, both beneficial and harmful to the virus, recognize and directly bind specific capsid surfaces. Unfortunately, our mechanistic understanding of host-capsid interactions is well behind that of our knowledge of apo capsid structure. This is because many capsid binding factors only recognize high-order capsid lattice patterns and do not show appreciable affinity for soluble capsid building blocks, such as CA dimers and hexamers. Without appropriate CA-binding partners, host factor-CA complexes cannot be formed in solution, and the vast array of solution-based biochemical and structural biology techniques cannot be applied. To overcome these limitations, I developed novel techniques to trap and stabilize CA oligomers in lattice-like fragments that are intermediates between unassembled and fully assembled capsid. These engineered lattice assemblies range in size from 50 kDa to 1 MDa (or 2-42 CA molecules) and exhibit every unique capsid lattice interface found in infectious virions. Many of the assemblies bridge the hexamer-hexamer and hexamer-pentamer surfaces formed by the CA C-terminal domains that have been previously impossible to capture. These lattice-intermediates enable analysis of elusive capsid-host factor binding events in solution-avoiding the pitfalls associated with capsid tubes and cones. I have used these assemblies to better define the unique capsid-binding modes of several well-studied, but poorly understood, restriction factors (TRIM5a, TRIMCyp, and MxB) and a recently discovered viral cofactor (FEZ1). Each of these factors demonstrated a unique capsid lattice-sensing ability that could only be defined with our novel CA assemblies. This work significantly expands our understanding of the diverse array of capsid-sensing motifs and targetable capsid surfaces. Besides mechanistic investigations, the advanced toolkit we have created will be valuable for searching for additional capsidbinding factors or designing specific capsid-targeting therapeutics to inhibit HIV-1 infectivity.
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