Maturation-induced Conformational Changes of HIV-1 Capsid Protein and Identification of Two High Affinity Sites for Cyclophilins in the C-terminal Domain

Endrich, Michael M.; Gehrig, Peter; Gehring, Heinz

doi:10.1074/jbc.274.9.5326

Cited by 37 publications

(39 citation statements)

References 34 publications

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“…The detailed mechanism of how cyclophilin A promotes HIV-1 replication is not understood, although several mechanisms have been discussed in recent years (5,6,22,23,28,30,(43)(44)(45). In light of the CA N ͞CypA cocrystal structure showing CA G89-P90 bound exclusively in the trans conformation (22), models depicting CypA as having a chaperone role in HIV-1 virulence have been suggested (28).…”

Section: Discussionmentioning

confidence: 99%

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Bosco

Eisenmesser

Pochapsky

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

204

211

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Packaging of cyclophilin A (CypA) into HIV-1 virions is essential for efficient replication; however, the reason for this is unknown. Incorporation is mediated through binding to the Gly-89 -Pro-90 peptide bond of the N-terminal domain of HIV-1 capsid (CA N ). Despite the fact that CypA is a peptidyl-prolyl cis͞trans isomerase, catalytic activity on CA N has not been observed previously. We show here, using NMR exchange spectroscopy, that CypA does not only bind to CA N but also catalyzes efficiently the cis͞trans isomerization of the Gly-89 -Pro-90 peptide bond. In addition, conformational changes in CA N distal to the CypA binding loop are observed on CypA binding and catalysis. The results provide experimental evidence for efficient CypA catalysis on a natively folded and biologically relevant protein substrate.

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Section: Discussionmentioning

confidence: 99%

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Bosco

Eisenmesser

Pochapsky

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

204

211

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“…Postassembly actions of CypA, such as uncoating, may be mediated via these new high-affinity binding sites of mature CA proteins. Supporting this hypothesis, several studies suggest that affinities of CypA for Gag and for CA are strikingly different (6,9,11). Specifically, Endrich and colleagues, using recombinant proteins, showed that the processing of immature CA, yielding mature CA, elicited conformational changes in its C-terminal domain.…”

Section: Resultsmentioning

confidence: 98%

“…They showed that CypA binds with a higher affinity to mature CA than to immature CA. They identified two new high-affinity binding interaction sites between CypA and mature CA in the C-terminal domain of CA around glycine 156-proline 157 and glycine 223-proline 224 (11). They proposed that these new binding sites represent loci upon which CypA acts postassembly.…”

Section: Resultsmentioning

confidence: 99%

trans-Complementation Rescue of Cyclophilin A-Deficient Viruses Reveals that the Requirement for Cyclophilin A in Human Immunodeficiency Virus Type 1 Replication Is Independent of Its Isomerase Activity

Saphire

Bobardt

Gallay

2002

J Virol

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Human immunodeficiency virus type 1 (HIV-1) requires the incorporation of cyclophilin A (CypA) for replication. CypA is packaged by binding to the capsid (CA) region of Gag. This interaction is disrupted by cyclosporine (CsA). Preventing CypA incorporation, either by mutations in the binding region of CA or by the presence of CsA, abrogates virus infectivity. Given that CypA possesses an isomerase activity, it has been proposed that CypA acts as an uncoating factor by destabilizing the shell of CA that surrounds the viral genome. However, because the same domain of CypA is responsible for both its isomerase activity and its capacity to be packaged, it has been challenging to determine if isomerase activity is required for HIV-1 replication. To address this issue, we fused CypA to viral protein R (Vpr), creating a Vpr-CypA chimera. Because Vpr is packaged via the p6 region of Gag, this approach bypasses the interaction with CA and allows CypA incorporation even in the presence of CsA. Using this system, we found that Vpr-CypA rescues the infectivity of viruses lacking CypA, either produced in the presence of CsA or mutated in the CypA packaging signal of CA. Furthermore, a Vpr-CypA mutant which has no isomerase activity and no capacity to bind to CA also rescues HIV-1 replication. Thus, this study demonstrates that the isomerase activity of CypA is not required for HIV-1 replication and suggests that the interaction of the catalytic site of CypA with CA serves no other function than to incorporate CypA into viruses.

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“…However, this does not preclude an interaction with CyPA. Since CyPA is known to interact with CA (14), it is possible that at least some of the CyPA is associated with the surface of the viral core and could be free to interact with Nef. However, the bulk of the Nef may remain contained within the core through other means.…”

Section: Vol 79 2005mentioning

confidence: 99%

Chimeric Human Immunodeficiency Virus Type 1 Virions That Contain the Simian Immunodeficiency Virus nef Gene Are Cyclosporin A Resistant

Khan

Jin

Miles

et al. 2005

J Virol

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We have previously shown that human immunodeficiency virus type 1 (HIV-1) virions which have their own nef gene deleted and are trans complemented to contain HIV-2 or simian immunodeficiency virus (SIV) Nef become resistant to treatment with cyclosporin A. To expand and confirm these studies, we have tested an HIV-1 isolate in which the HIV-1 nef gene has been replaced by the nef gene from SIV in a multiround infectivity assay using more physiologically relevant cell types. Our results confirm that HIV-1 virions that contain SIV nef can replicate in a cyclophilin-independent fashion.

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Maturation-induced Conformational Changes of HIV-1 Capsid Protein and Identification of Two High Affinity Sites for Cyclophilins in the C-terminal Domain

Cited by 37 publications

References 34 publications

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

trans-Complementation Rescue of Cyclophilin A-Deficient Viruses Reveals that the Requirement for Cyclophilin A in Human Immunodeficiency Virus Type 1 Replication Is Independent of Its Isomerase Activity

Chimeric Human Immunodeficiency Virus Type 1 Virions That Contain the Simian Immunodeficiency Virus nef Gene Are Cyclosporin A Resistant

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