Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions.
The entry of human immunodeficiency virus (HIV-1) into cells is initiated by binding of the gp120 exterior envelope glycoprotein to the receptor, CD4. How does CD4 binding trigger conformational changes in gp120 that allow the gp41 transmembrane envelope glycoprotein to mediate viral-cell membrane fusion? The transition from the unliganded to the CD4-bound state is regulated by two potentially flexible topological layers (layers 1 and 2) in the gp120 inner domain. Both layers apparently contribute to the noncovalent association of unliganded gp120 with gp41. After CD4 makes initial contact with the gp120 outer domain, layer 1-layer 2 interactions strengthen gp120-CD4 binding by reducing the off rate. Layer 1-layer 2 interactions also destabilize the activated state induced on HIV-1 by treatment with soluble CD4. Thus, despite lack of contact with CD4, the gp120 inner-domain layers govern CD4 triggering by participating in conformational transitions within gp120 and regulating the interaction with gp41.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
Andrés
A
Finzi
Shi-Hua
SH
Xiang
Beatriz
B
Pacheco
Liping
L
Wang
Jessica
J
Haight
Aemro
A
Kassa
Brenda
B
Danek
Marie
M
Pancera
Peter D
PD
Kwong
Joseph
J
Sodroski
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016333:HIV Protease / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D053586:Virus Internalization
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D008024:Ligands; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; D016333:HIV Protease