Epstein–Barr Virus Latent Membrane Protein 2
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Epstein–Barr virus (EBV) latent membrane protein 2 (LMP2) are two
viral protein The term viral protein refers to both the products of the genome of a virus and any host proteins incorporated into the viral particle. Viral proteins are grouped according to their functions, and groups of viral proteins include structural protei ...
s of the
Epstein–Barr virus The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
. LMP2A/LMP2B are transmembrane proteins that act to block
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
signaling. LMP2A is a
transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...
that inhibits normal B-cell signal transduction by mimicking an activated
B-cell receptor The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 Transmembrane protein, transmemb ...
(BCR). The
N-terminus 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 amin ...
domain of LMP2A is
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
phosphorylated and associates with Src family protein tyrosine kinases (PTKs) as well as spleen tyrosine kinase ( Syk). PTKs and Syk are associated with BCR
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
.


LMP2 gene structure and expression

Latent Membrane Protein 2 (LMP2) is a rightward transcribing gene. LMP2's transcript originates across the fused terminal repeats in sequences at opposite ends of the
genome 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 genes, other functional regions of the genome such as ...
. hours after infection, the genome circularizes and the
open reading frame In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames ...
is created. 1.7 kb and 2.0 kb messages are created by alternative promoter usage and differ only in the sequences of the first
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
. These messages are expressed in Epstein-Barr Virus transformed lymphoblastoid cell cultures. The ratio of these messages varies widely and unpredictably suggesting little co-ordinate control of promoter activity or
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
abundance. Residues 497 (LMP2A) and 378 (LMP2B) are encoded by these two messages. These two iso forms of LMP2 only differ in that LMP2A contains an extra 119 residue N-terminal domain encoded in exon 1. LMP2B's first exon is non coding. Initiation of translation is presumed to occur at the first available ethioninethat is in-frame in exon two. Twelve membrane spanning segments ending with a short 28 residue COOH tail are common to both proteins in residue 379.


LMP2A protein interactions

The 119 amino-terminal cytoplasmic domain of LMP2A has several motifs that mediate interactions between proteins, including eight tyrosine residues. Two motifs that are centered on Y74 and Y85 are spaced 7 residues apart to form an immunoreceptor tyrosine-based activation motif (ITAM) commonly found in Fc receptors and signal molecules of B-cell and T-cell receptors. Receptor docking with molecules containing cytoplasmic tyrosine kinases is governed by
Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
of ITAM motifs. In lymphoblastoid cell cultures, Syk tyrosine kinases have been found in LMP2A immunoprecipitates following
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
kinase reactions followed by Syk
antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
reimunnoprecipitation. Affinity precipitation experiments have shown that Syk interacts with phosphorylated
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s corresponding to the LMP2A-ITAM complex. Residues for Syk binding have been discovered by inducing
point mutations A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
in Y74F and Y85F point. Tyrosine kinase
LYN Lyn or LYN may refer to: People * Lyn (singer), South Korean singer * Lyn (gamer), South Korean ''Warcraft III'' player * Lyn (given name) * Lyn (surname) In science and technology * Lynx (constellation), standard abbreviation * Lyn (locomotive ...
has also been detected in immunoprecipitates from transiently transfected B cells at residue Y112. Constitutive phosphorylation occurs on
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
,
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
and
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...
residues.


LMP2A function

Epstein–Barr virus The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
(EBV) establishes a lifelong
latent Latency or latent may refer to: Engineering * Latency (engineering), a measure of the time delay experienced by a system ** Latency (audio), the delay between the moment an audio signal is triggered and the moment it is produced or received ** Mec ...
infection in
B lymphocytes B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
. Viral LMP2A mRNA is frequently detected in peripheral blood B lymphocytes and the protein is often present in tumor biopsies from EBV malignancies. This suggests LMP2A plays an important role in viral latency, as well as in progression of EBV related diseases such as
Burkitt's lymphoma Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...
,
Nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess (fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...
, and
Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...
. Portis and Longnecker (2004) have found that LMP2A induces activation of B cell Ras pathway in vivo. Using down stream inhibitors of Ras signaling components, they demonstrated activation of
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tra ...
pathway is involved in LMP2A mediated B cell survival and resistance to
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
Caldwell et al. (1998) demonstrated the ability of LMP2A to provide survival signals to B-cells in vivo where expression of an LMP2A
transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
in mice disrupts with normal B-cell development. This results in BCR-negative cells being able to exit the bone marrow and survive in peripheral lymphoid organs. B-cells from LMP2A transgenic E line undergo immunoglobulin light chain rearrangements, but not heavy chain rearrangement. This indicates that LMP2A signaling bypasses the requirement for immunoglobulin recombination and allows immunoglobulin M-negative type cells to bypass apoptosis, allowing them to colonize peripheral lymphoid organs.


LMP2B

Eight exons of LMP2 isoforms encode 12 membrane spanning segments that are connected by short
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
loops and ends with a 27
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
cytoplasmic
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
domain. LMP2B, unlike LMP2A, does not contain the N-terminal 119
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
cytoplasmic signaling domain. Most LMP2 research is focused on LMP2A
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
due to its unique expression in latently infected B lymphocytes
in situ is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...
. LMP2B protein function is unknown. There has not been a comprehensive phenotypic analysis of the LMP2B isoform because of its
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
character. While the role of LMP2B in
pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...
remains uncertain, homology studies comparing the LMP2 gene of EBV with Rhesus and
Baboon Baboons are primates comprising the biology, genus ''Papio'', one of the 23 genera of Old World monkeys, in the family Cercopithecidae. There are six species of baboon: the hamadryas baboon, the Guinea baboon, the olive baboon, the yellow ba ...
Lymphocryptovirus ''Lymphocryptovirus'' is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Gammaherpesvirinae''. This genus includes the human-infecting ''Human gammaherpesvirus 4'' (Epstein–Barr virus), as ...
, have revealed promoter regulatory elements, Epstein–Barr nuclear antigen-2 responsiveness, and the ability to make LMP2B transcripts are conserved. This implies that an unrecognized role for LMP2B in the EBV life cycle has yet to be determined.


References

{{DEFAULTSORT:Epstein-Barr virus latent membrane protein 2 Viral structural proteins Epstein–Barr virus