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molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
, Tat is a protein that is encoded for by the ''tat''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ...
in
HIV-1 The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey ...
. Tat is a
regulatory protein Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
that drastically enhances the efficiency of viral
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, resulting in increased transcription of all HIV genes, providing a
positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in th ...
cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response. Tat also appears to play a more direct role in the HIV disease process. The protein is released by infected cells in culture, and is found in the blood of HIV-1 infected patients. It can be absorbed by cells that are not infected with HIV, and can act directly as a
toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849� ...
producing cell death via
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
in uninfected "bystander"
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
s, assisting in progression toward
AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
. By antagonizing the
CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemoki ...
receptor, Tat also appears to selectively encourage the reproduction of less virulent M-
tropic The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in the Southern Hemisphere at S. The tropics are also referred to ...
(
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
-tropic) strains of HIV (which use the CCR5 receptor) early in the course of infection, allowing the more rapidly pathogenic T-tropic (
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
-tropic) strains (which use the CXCR4 receptor) to emerge later after mutating from M-tropic strains.


Function and mechanism

Like other
lentivirus ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
es, HIV-1 encodes a trans-activating
regulatory Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...
protein (Tat), which is essential for efficient
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
of the viral
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
. Tat acts by binding to an RNA
stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when ...
structure, the trans-activation response element (TAR), found at the 5′ ends of nascent HIV-1 transcripts. In binding to TAR, Tat alters the properties of the transcription complex, recruits the positive transcription elongation complex ( P-TEFb) of cellular CDK9 and cyclin T1, and hence increases the production of full-length viral RNA. Tat protein also associates with
RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukar ...
complexes during early transcription elongation after the promoter clearance and before the synthesis of full-length TAR RNA transcript. This interaction of Tat with RNA polymerase II elongation complexes is P-TEFb-independent. There are two Tat
binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
s on each transcription elongation complex; one is located on TAR RNA and the other one on RNA polymerase II near the exit site for nascent mRNA transcripts, which suggests the involvement of two Tat molecules in facilitating one round of HIV-1 mRNA synthesis. The minimum Tat
sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is call ...
that can mediate specific TAR binding ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
'' has been mapped to a basic
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function ** Domain of holomorphy of a function * ...
of 10
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s, comprising mostly Arg and Lys residues. Regulatory activity, however, also requires the 47
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the am ...
residues, which
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with components of the transcription complex and function as a transcriptional activation domain. Tat also uses an unusual transcellular transport pathway. Firstly, it binds with high affinity to
Phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PI(4,5)P2), found on the inner surface of the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
, to facilitate Tat recruitment. Tat then crosses the plasma membrane to reach the extracellular space. Tat secretion by infected cells is highly active, and export is the major destination for HIV-1 Tat.


Structure

The basic region of HIV-Tat protein is suggested to form an
alpha helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...
. The basic region is involved in RNA (TAR, trans-activation response element) binding and Tat proteins thus belong to the family of arginine-rich motif (ARM) RNA binding proteins.


Protein transduction domain

Tat contains a protein transduction
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function ** Domain of holomorphy of a function * ...
(PTD), which is also known as a cell-penetrating peptide. Originally characterised by Frankel and Pabo (1988) and Green and Loewenstein (1988), this domain allows Tat to enter cells by crossing the cell membrane. The amino acid sequence of the PTD is YGRKKRRQRRR. This cationic eleven-amino-acid peptide is sufficient to target large molecules, including nanoparticles that display it, for transduction into cells. Unlike the heparinase-independent transduction of isolated PTD polypeptide, internalization of full-length Tat is mediated by interactions with negatively-charged heparan sulfate
proteoglycans Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whi ...
at the cell surface. This translocation is partly mediated by potocytosis. The nuclear localisation signal found within the PTD, GRKKR, mediates further translocation of Tat into the cell nucleus. The biological role of this domain and exact mechanism of transfer is unknown.


Clinical significance

Inhibition of Tat has been investigated. It has been suggested that Tat antagonists may be of use in the treatment of HIV infections. Biosantech has developed a novel vaccine called Tat Oyi, which aims at the Tat protein. The company's HIV vaccine candidate is not toxic to 48 HIV-positive patients enrolled in a double-blind study taking place in France. A Phase I/IIa study, published in 2016, shows a reduction in viral RNA for one of three doses tested. A dose-dependent response was not observed, raising questions about the robustness of the findings.


References

{{DISPLAYTITLE:Tat (HIV) HIV/AIDS Viral regulatory and accessory proteins