1ceu
From Proteopedia
NMR STRUCTURE OF THE (1-51) N-TERMINAL DOMAIN OF THE HIV-1 REGULATORY PROTEIN
Structural highlights
FunctionVPR_HV1B9 Involved in the transport of the viral pre-integration (PIC) complex to the nucleus during the early stages of the infection. This function is crucial for viral infection of non-dividing macrophages. May interact with karyopherin alpha/KPNA1 and KPNA2 to increase their affinity for proteins containing basic-type nuclear localization signal, including the viral matrix protein MA, thus facilitating the translocation of the viral genome into the nucleus. May also act directly at the nuclear pore complex, by binding nucleoporins phenylalanine-glycine (FG)-repeat regions (By similarity). May target specific host proteins for degradation by the 26S proteasome. Acts by associating with the cellular CUL4A-DDB1 E3 ligase complex through direct interaction with host VPRPB/DCAF-1. This change in the E3 ligase substrate specificity would result in cell cycle arrest or apoptosis in infected cells. Prevents infected cells from undergoing mitosis and proliferating, by inducing arrest or delay in the G2 phase of the cell cycle. This arrest creates a favorable environment for maximizing viral expression and production by rendering the HIV-1 LTR transcriptionally more active. In this context, Vpr stimulates gene expression driven by the HIV-1 LTR by interacting with human SP1, TFIIB and TFIID. Cell cycle arrest reportedly occurs within hours of infection and is not blocked by antiviral agents, suggesting that it is initiated by the Vpr carried into the virion. Additionally, Vpr induces apoptosis in a cell cycle dependent manner suggesting that these two effects are mechanistically linked. Interacts with mitochondrial permeability transition pore complex (PTPC). This interaction induces a rapid dissipation of the mitochondrial transmembrane potential, and mitochondrial release of apoptogenic proteins such as cytochrome C or apoptosis inducing factors. Detected in the serum and cerebrospinal fluid of AIDS patient, Vpr may also induce cell death to bystander cells (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulatory gene product, Vpr (viral protein of regulation, 96 amino acid residues), which is incorporated into virions, in quantities equivalent to those of the viral Gag proteins. In the infected cells, Vpr is believed to function in the early phase of HIV-1 replication, including nuclear migration of preintegration complex, transcription of the provirus genome and viral multiplication by blocking cells in the G2 phase. Vpr has a critical role in long-term AIDS disease by inducing infection in nondividing cells such as monocytes and macrophages. Mutations have suggested that the N-terminal domain of Vpr encompassing the first 40 residues could be required for nuclear localization, packaging into virions and binding of transcription factor (TFIIB, Sp1), viral proteins (p6) and cellular proteins (RIP1, UNG, karyopherins). To gain insight into the structure-function relationship of Vpr, (1-51)Vpr was synthesized and its structure analyzed by circular dichroism and two-dimensional 1H NMR in aqueous trifluoroethanol (30%) solution and refined by restrained molecular dynamics. The structure is characterized by three turns around the first three prolines, Pro5, Pro10, Pro14, followed by a long amphipathic alpha helix-turn-alpha helix (Asp17-Ile46) motif ended by a turn extending from Tyr47 to Thr49. The alpha helix-turn-alpha helix motif and the amphipathic helix are well known for being implicated in protein-protein or protein-nucleic acid interaction. Therefore structural characteristics of the (1-51) N-terminal fragment of Vpr could explain why this region of Vpr plays a role in several biological functions of this protein. NMR structure of the (1-51) N-terminal domain of the HIV-1 regulatory protein Vpr.,Wecker K, Roques BP Eur J Biochem. 1999 Dec;266(2):359-69. PMID:10561576[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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