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A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef

HIV-1 Nef modulates disease progression through interactions with over 30 host proteins. Individual chains fold into membrane-interacting N-terminal and C-terminal core (Nef(core)) domains respectively. Nef exists as small oligomers near membranes and associates into higher oligomers such as tetrame...

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Autores principales: Singh, Pankaj, Yadav, Gaya Prasad, Gupta, Sudeepti, Tripathi, Anil Kumar, Ramachandran, Ravishankar, Tripathi, Raj Kamal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206816/
https://www.ncbi.nlm.nih.gov/pubmed/22073177
http://dx.doi.org/10.1371/journal.pone.0026629
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author Singh, Pankaj
Yadav, Gaya Prasad
Gupta, Sudeepti
Tripathi, Anil Kumar
Ramachandran, Ravishankar
Tripathi, Raj Kamal
author_facet Singh, Pankaj
Yadav, Gaya Prasad
Gupta, Sudeepti
Tripathi, Anil Kumar
Ramachandran, Ravishankar
Tripathi, Raj Kamal
author_sort Singh, Pankaj
collection PubMed
description HIV-1 Nef modulates disease progression through interactions with over 30 host proteins. Individual chains fold into membrane-interacting N-terminal and C-terminal core (Nef(core)) domains respectively. Nef exists as small oligomers near membranes and associates into higher oligomers such as tetramers or hexadecamers in the cytoplasm. Earlier structures of the Nef(core) in apo and complexed forms with the Fyn-kinase SH3 domain revealed dimeric association details and the role of the conserved PXXP recognition motif (residues 72–78) of Nef in SH3-domain interactions. The crystal structure of the tetrameric Nef reported here corresponds to the elusive cytoplasmic stage. Comparative analyses show that subunits of Nef(core) dimers (open conformation) swing out with a relative displacement of ∼22 Å and rotation of ∼174° to form the ‘closed’ tetrameric structure. The changes to the association are around Asp125, a conserved residue important for viral replication and the important XR motif (residues 107–108). The tetramer associates through C4 symmetry instead of the 222 symmetry expected when two dimers associate together. This novel dimer-tetramer transition agrees with earlier solution studies including small angle X-ray scattering, analytical ultracentrifugation, dynamic laser light scattering and our glutaraldehyde cross-linking experiments. Comparisons with the Nef(core)—Fyn-SH3 domain complexes reveal that the PXXP motif that interacts with the SH3-domain in the dimeric form is sterically occluded in the tetramer. However the 151–180 loop that is distal to the PXXP motif and contains several protein interaction motifs remains accessible. The results suggest how changes to the oligomeric state of Nef can help it distinguish between protein partners.
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spelling pubmed-32068162011-11-09 A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef Singh, Pankaj Yadav, Gaya Prasad Gupta, Sudeepti Tripathi, Anil Kumar Ramachandran, Ravishankar Tripathi, Raj Kamal PLoS One Research Article HIV-1 Nef modulates disease progression through interactions with over 30 host proteins. Individual chains fold into membrane-interacting N-terminal and C-terminal core (Nef(core)) domains respectively. Nef exists as small oligomers near membranes and associates into higher oligomers such as tetramers or hexadecamers in the cytoplasm. Earlier structures of the Nef(core) in apo and complexed forms with the Fyn-kinase SH3 domain revealed dimeric association details and the role of the conserved PXXP recognition motif (residues 72–78) of Nef in SH3-domain interactions. The crystal structure of the tetrameric Nef reported here corresponds to the elusive cytoplasmic stage. Comparative analyses show that subunits of Nef(core) dimers (open conformation) swing out with a relative displacement of ∼22 Å and rotation of ∼174° to form the ‘closed’ tetrameric structure. The changes to the association are around Asp125, a conserved residue important for viral replication and the important XR motif (residues 107–108). The tetramer associates through C4 symmetry instead of the 222 symmetry expected when two dimers associate together. This novel dimer-tetramer transition agrees with earlier solution studies including small angle X-ray scattering, analytical ultracentrifugation, dynamic laser light scattering and our glutaraldehyde cross-linking experiments. Comparisons with the Nef(core)—Fyn-SH3 domain complexes reveal that the PXXP motif that interacts with the SH3-domain in the dimeric form is sterically occluded in the tetramer. However the 151–180 loop that is distal to the PXXP motif and contains several protein interaction motifs remains accessible. The results suggest how changes to the oligomeric state of Nef can help it distinguish between protein partners. Public Library of Science 2011-11-02 /pmc/articles/PMC3206816/ /pubmed/22073177 http://dx.doi.org/10.1371/journal.pone.0026629 Text en Singh et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Singh, Pankaj
Yadav, Gaya Prasad
Gupta, Sudeepti
Tripathi, Anil Kumar
Ramachandran, Ravishankar
Tripathi, Raj Kamal
A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title_full A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title_fullStr A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title_full_unstemmed A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title_short A Novel Dimer-Tetramer Transition Captured by the Crystal Structure of the HIV-1 Nef
title_sort novel dimer-tetramer transition captured by the crystal structure of the hiv-1 nef
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206816/
https://www.ncbi.nlm.nih.gov/pubmed/22073177
http://dx.doi.org/10.1371/journal.pone.0026629
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