Biochemical and structural characterization of the human immunodeficiency virus type1 capsid protein and its interaction with human cyclophilin A

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Yoo, Sanghee
Contributor Worthylake, David; Vajdos, Felix; Gamble, Theresa; Hill Christopher; Gitti, Rossi; Lee, Brian; Summers, Mike; Yen, Chin-yah; Mysxka, David
Title Biochemical and structural characterization of the human immunodeficiency virus type1 capsid protein and its interaction with human cyclophilin A
Date 1997-12
Description The Human Immunodeficiency Virus Type 1 (HIV-1) contains a characteristic cone-shaped structure that surrounds the viral RNA genome at the center of the mature virion. This structure is composed of the viral capsid protein (CA). Capsid also plays a major role early in viral assembly as a domain of the Gag polyprotein. Finally, capsid also interacts with the cellular peptidyl prolyl isomerase, cyclophilin A (CypA), which is thought to function in uncoating of the capsid structure. To understand the various functions of the HIV-1 capsid protein and its interactions with CypA, recombinant capsid proteins and their complexes with cyclophilin A were characterized biochemically and structurally. The capsid protein contains two independent folding domains, an amino-terminal CypA binding domain (residues 1- ~ 151; CA/151) and a carboxy-terminal dimerization domain (residues ~ 151-231 CA/151-231). The intact capsid protein dimerizes with K/d = 1.8 ± 0.1 x 10/-5 M, and all of the dimer contacts are located in the C-terminal domain. The crystal structure of the CA/151-231 dimer revealed that the dimer interface is composed of a hydrophobic core surrounded by a ring of complementary hydrophilic residues. The amino-terminal domain of CA is monomeric in solution and contains the entire cyclophilin A binding site (K/d = 1.6 ± 0.4 x 0/-5 M). The co-crystal structure of CA/151/CypA was determined and revealed that CypA binds exclusively to residues in an exposed loop. A central loop dipeptide, Gly89-Pro90 forms the primary binding determinant for CypA recognition, with Gly89 allowing Pro90 to bind in an unprecedent trans conformation. CypA has been proposed to function in capsid core disassembly. In the CA/151/CYPA structure, capsid proteins associate into planar strips, but the stoichiometrically bound CypA proteins seem to block further interactions between these strips. We proposed that in the virus, the substoichiometric levels of CypA may simply weaken CA-CA strip interactions and thereby facilitate core disassembly. Taken together, our studies reveal the multiple interaction interfaces of the HIV-1 capsid protein that are important for its assembly into viral cores of the correct morphology. These studies have also provided plausible models for the dynamic processes of viral core assembly and disassembly.
Type Text
Publisher University of Utah
Subject Host-Virus Relatonships
Subject MESH HIV; Viral Proteins
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Biochemical and structural characterization of the human immunodeficiency virus type1 capsid protein and its interaction with human cyclophilin A." Spencer S. Eccles Health Sciences Library. Print version of "Biochemical and structural characterization of the human immunodeficiency virus type1 capsid protein and its interaction with human cyclophilin A." available at J. Willard Marriott Library Special Collection. QR6.5 1997.Y66.
Rights Management © Sanghee Yoo.
Format Medium application/pdf
Format Extent 3,772,991 bytes
Identifier undthes,5440
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 3,773,011 bytes
ARK ark:/87278/s65x2br4
Setname ir_etd
Date Created 2012-04-24
Date Modified 2021-05-06
ID 191186
Reference URL https://collections.lib.utah.edu/ark:/87278/s65x2br4
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