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42-805: The Vpu gene is found exclusively in HIV-1 and some HIV-1-related simian immunodeficiency virus ( SIV ) isolates, such as SIV cpz , SIV gsn , and SIV mon , but not in HIV-2 or the majority of SIV isolates. Structural similarities between Vpu and another small viral protein, M2, encoded by influenza A virus were first noted soon after the discovery of Vpu. Since then, Vpu has been shown to form cation-selective ion channels when expressed in Xenopus oocytes or mammalian cells and also when purified and reconstituted into planar lipid bilayers . Vpu also permeabilizes membranes of bacteria and mammalian cells to small molecules. Therefore, it

84-513: A DNA intermediate). The ICTVdB code of SIV is 61.0.6.5.003. Although HIV-1 and HIV-2 cladistically fall into SIV, ICTV considers them distinct species from ordinary, non-human-infecting SIV. HIV-1 cpzPtt gor cpzPts drl mnd2 rcm agi HIV-2 mac mne stm smm gri ver tan sab lho sun prg mnd1 wrc olc trc krc gsn mus2 col kcol1 kcol2 blc mon mus1 reg tal asc bkm deb blu den syk wol While human immunodeficiency virus has

126-483: A basal branch relative to extant SIVs. Ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential , shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane , controlling the flow of ions across secretory and epithelial cells , and regulating cell volume. Ion channels are present in

168-428: A circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer . For most voltage-gated ion channels , the pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on. Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across

210-426: A limited number of subtypes, SIV is now known to infect a few dozen species of non-human primates, and distinct strains are often associated with each species, or with a set of closely related species. The thus far categorized ~40 strains are divided into five distinct groups and one subgroup: In addition to the subgroups defined for extent SIVs, two endogenous SIVs are found in prosimian lemurs. These paleo-SIVs form

252-486: A putative glycosylphosphatidylinositol anchor (GPI). At the cell surface, BST2 resides in lipid rafts through the GPI anchor, whereas its TM domain lies outside them, indirectly interacting with the actin cytoskeleton. Vpu primary site of action is the plasma membrane, where this protein targets cell-surface BST-2 through their mutual TM-to-TM binding, leading to lysosomes, partially dependent on βTrCP. Viral protein "u" (Vpu)

294-508: A share of the 2003 Nobel Prize in Chemistry . Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example

336-545: A species of retrovirus in the Primate group of genus Lentivirus along with the human viruses HIV-1 and HIV-2 that cause AIDS, and a few other viruses that infect other primates. Related viruses in other groups in the genus infect other mammals like sheep and goats, horses, cattle, cats, and a few others. The genus is one of six genera in subfamily orthoretrovirinae , which together with genus Spumavirus form family retroviridae of all RNA retroviruses (RNA viruses which use

378-420: A third α-helical domain in the transmembrane domain of Vpu, which could play an important role in the formation of ion channels . Simian immunodeficiency virus Simian immunodeficiency virus ( SIV ) is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates . Based on analysis of strains found in four species of monkeys from Bioko Island , which

420-436: A wide variety of biological processes that involve rapid changes in cells, such as cardiac , skeletal , and smooth muscle contraction , epithelial transport of nutrients and ions, T-cell activation, and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target. There are over 300 types of ion channels just in the cells of the inner ear. Ion channels may be classified by

462-495: Is an oligomeric , 81-amino acid type I membrane protein (16 kDa) that is translated from vpu-env bicistronic mRNA. The N-terminus of Vpu encoding the transmembrane (TM) anchor represents an active domain important for the regulation of virus release but not CD4 degradation. The C-terminal cytoplasmic domain (54 residues) that contains a pair of serine residues (at positions 52 and 56) constitutively phosphorylated by casein kinase 2 . The phosphorylation of two serine residues in

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504-400: Is called selective permeability . The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium . However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge: positive ( cations ) or negative ( anions ). Ions often move through the segments of

546-530: Is considered a member of the Viroporins family. Vpu and Env are expressed from the same bicistronic mRNA in a Rev-dependent manner, presumably by leaky scanning of ribosomes through the vpu initiation codon . In fact Vpu gene overlaps at its 3′-end with the env gene. Several HIV-1 isolates were found to carry point mutations in the Vpu translation initiation codon but have otherwise intact vpu genes. Since removal of

588-418: Is referred to as channelomics . There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins: Ion channels are located within the membrane of all excitable cells, and of many intracellular organelles . They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. This characteristic

630-765: Is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003. One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology , biochemistry , gene sequence comparison and mutagenesis . Channels can have single (CLICs) to multiple transmembrane (K channels, P2X receptors, Na channels) domains which span plasma membrane to form pores. Pore can determine

672-401: The synapses , channels are especially prominent components of the nervous system . Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails, and others) work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in

714-456: The BST-2 transmembrane domain is crucial for interference by Vpu. The interaction of Vpu and BST-2 results in the downregulation of BST-2 from the cell surface. BST-2, which is an interferon (IFN)-inducible cell surface protein, appears to “tether” HIV to the cell in the absence of Vpu. BST-2 is a heavily glycosylated 29- to 33-kDa integral membrane protein with both a transmembrane domain and

756-457: The British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize -winning research on the action potential , published in 1952. They built on the work of other physiologists, such as Cole and Baker's research into voltage-gated membrane pores from 1941. The existence of ion channels was confirmed in the 1970s by Bernard Katz and Ricardo Miledi using noise analysis . It

798-399: The Vpu initiation codon results in increased expression of the downstream env gene, it is possible that HIV-1 actually uses this mechanism as a molecular switch to regulate the relative expression of Vpu or Env in infected cells. The possible benefits of such a regulation are unclear. Two main functions have been assigned to the Vpu protein. The first function is known to induce degradation of

840-500: The anion-permeable γ-aminobutyric acid-gated GABA A receptor . Ion channels activated by second messengers may also be categorized in this group, although ligands and second messengers are otherwise distinguished from each other. This group of channels opens in response to specific lipid molecules binding to the channel's transmembrane domain typically near the inner leaflet of the plasma membrane. Phosphatidylinositol 4,5-bisphosphate ( PIP 2 ) and phosphatidic acid ( PA ) are

882-410: The basis of localization, ion channels are classified as: Some ion channels are classified by the duration of their response to stimuli: Channels differ with respect to the ion they let pass (for example, Na , K , Cl ), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. Channels belonging to the largest class, which includes

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924-663: The best-characterized lipids to gate these channels. Many of the leak potassium channels are gated by lipids including the inward-rectifier potassium channels and two pore domain potassium channels TREK-1 and TRAAK. KCNQ potassium channel family are gated by PIP 2 . The voltage activated potassium channel (Kv) is regulated by PA. Its midpoint of activation shifts +50 mV upon PA hydrolysis, near resting membrane potentials. This suggests Kv could be opened by lipid hydrolysis independent of voltage and may qualify this channel as dual lipid and voltage gated channel. Gating also includes activation and inactivation by second messengers from

966-441: The channel pore in a single file nearly as quickly as the ions move through the free solution. In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force. Ion channels are integral membrane proteins , typically formed as assemblies of several individual proteins. Such "multi- subunit " assemblies usually involve

1008-427: The channels. For example, voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel. Voltage-gated ion channels open and close in response to membrane potential . Also known as ionotropic receptors , this group of channels open in response to specific ligand molecules binding to

1050-446: The cytoplasmic domain is critical for CD4 degradation in the ER. Based on 2D 1H NMR spectroscopy of a peptide corresponding to the cytoplasmic domain of Vpu, it was proposed that the cytoplasmic domain of Vpu contains two α-helical domains, helix-1 and helix-2, which are connected by an unstructured region containing the two conserved phosphoseryl residues. In addition, computer models predict

1092-446: The extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of such channels include the cation-permeable nicotinic acetylcholine receptors , ionotropic glutamate-gated receptors , acid-sensing ion channels (ASICs), ATP-gated P2X receptors , and

1134-733: The hosts to the virus. Extensive studies in sooty mangabeys have established that SIVsmm infection does not cause any disease in these primates, despite high levels of circulating virus. Regulation of the activity of the CCR5 coreceptor is one of the natural strategies to avoid disease in some natural host species of SIV. Unlike SIVsmm infection in sooty mangabeys, a recent study of SIVcpz in wild living chimpanzees suggests that infected chimpanzees experience an AIDS-like illness similar to HIV-1 infected humans. The later stages of SIV infection develop into sAIDS, much like how HIV infection develops into AIDS. The simian (monkey-hosted) immunodeficiency viruses are

1176-433: The inside of the cell membrane – rather than from outside the cell, as in the case for ligands. Ion channels are also classified according to their subcellular localization. The plasma membrane accounts for around 2% of the total membrane in the cell, whereas intracellular organelles contain 98% of the cell's membrane. The major intracellular compartments are endoplasmic reticulum , Golgi apparatus , and mitochondria . On

1218-407: The membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters . The study of ion channels often involves biophysics , electrophysiology , and pharmacology , while using techniques including voltage clamp , patch clamp , immunohistochemistry , X-ray crystallography , fluoroscopy , and RT-PCR . Their classification as molecules

1260-512: The nature of their gating , the species of ions passing through those gates, the number of gates (pores), and localization of proteins. Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a specific kind of current. Absence or mutation of one or more of the contributing types of channel subunits can result in loss of function and, potentially, underlie neurologic diseases. Ion channels may be classified by gating, i.e. what opens and closes

1302-472: The opening or activation of specific ion channels. These are classified by the channel on which they act: There are a number of disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic and autoimmune disorders of ion channels and their modifiers are known as channelopathies . See Category:Channelopathies for a full list. The fundamental properties of currents mediated by ion channels were analyzed by

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1344-416: The other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin ) and requires Vpu’s TM domain. however, the exact mechanism of how Vpu counteracts BST-2 is still unclear. In the absence of Vpu, tetherin binds to the viral envelope and ties it to the cell membrane and other viral particles, impeding release of the viral particles. Recent data suggest that

1386-402: The selectivity of the channel. Gate can be formed either inside or outside the pore region. Chemical substances can modulate the activity of ion channels, for example by blocking or activating them. A variety of ion channel blockers (inorganic and organic molecules) can modulate ion channel activity and conductance. Some commonly used blockers include: Several compounds are known to promote

1428-473: The species barrier into human hosts multiple times throughout history, but it was not until recently, after the advent of modern transportation and global commuterism , that it finally took hold, spreading beyond localized decimations of a few individuals or single small tribal populations. Unlike HIV-1 and HIV-2 infections in humans, SIV infections in their natural simian non-human hosts appear in many cases to be non-pathogenic due to evolutionary adaptation of

1470-462: The throughput in ion channel screening. The Nobel Prize in Chemistry for 2003 was awarded to Roderick MacKinnon for his studies on the physico-chemical properties of ion channel structure and function, including x-ray crystallographic structure studies. Roderick MacKinnon commissioned Birth of an Idea , a 5-foot (1.5 m) tall sculpture based on the KcsA potassium channel . The artwork contains

1512-483: The two HIV viruses. The most likely route of transmission of HIV-1 to humans involves contact with the blood of chimps and gorillas that are often hunted for bushmeat in Africa. Four subtypes of HIV-1 (M, N, O, and P) likely arose through four separate transmissions of SIV to humans, and the resulting HIV-1 group M strain most commonly infects people worldwide. Therefore, it is theorized that SIV may have previously crossed

1554-545: The viral receptor molecule CD4, and the second function is to enhance the release of newly formed virions from the cell surface. Vpu accomplishes these two functions through two distinct mechanisms. In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes . This requires signals located in Vpu’s cytoplasmic domain. Enhancement of virus release on

1596-427: The voltage-gated channels that underlie the nerve impulse, consist of four or sometimes five subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The existence and mechanism for ion selectivity

1638-466: Was finally confirmed when the first structure of an ion channel was elucidated. A bacterial potassium channel KcsA, consisting of just the selectivity filter, "P" loop, and two transmembrane helices was used as a model to study the permeability and the selectivity of ion channels in the Mackinnon lab. The determination of the molecular structure of KcsA by Roderick MacKinnon using X-ray crystallography won

1680-480: Was first postulated in the late 1960s by Bertil Hille and Clay Armstrong . The idea of the ionic selectivity for potassium channels was that the carbonyl oxygens of the protein backbones of the "selectivity filter" (named by Bertil Hille ) could efficiently replace the water molecules that normally shield potassium ions, but that sodium ions were smaller and cannot be completely dehydrated to allow such shielding, and therefore could not pass through. This mechanism

1722-492: Was isolated from the mainland by rising sea levels about 11,000 years ago, it has been concluded that SIV has been present in monkeys and apes for at least 32,000 years, and probably much longer. Virus strains from three of these primate species, SIVsmm in sooty mangabeys , SIVgor in gorillas and SIVcpz in chimpanzees , are believed to have crossed the species barrier into humans, resulting in HIV-2 and HIV-1 respectively,

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1764-456: Was then shown more directly with an electrical recording technique known as the " patch clamp ", which led to a Nobel Prize to Erwin Neher and Bert Sakmann , the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these proteins work. In recent years the development of automated patch clamp devices helped to increase significantly

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