![Antibody Structure and Antigen Binding Regions](https://upload.wikimedia.org/wikipedia/commons/8/8d/Antibody_Structure_and_Antigen_Binding_Regions.jpg)
In
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 physi ...
, a framework region is a subdivision of the
variable region (Fab) of the
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. The variable region is composed of seven amino acid regions, four of which are framework regions and three of which are hypervariable regions. The framework region makes up about 85% of the variable region.
Located on the tips of the Y-shaped molecule, the framework regions are responsible for acting as a scaffold for the
complementarity determining regions
Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs co ...
(CDR), also referred to as
hypervariable regions, of the Fab. These CDRs are in direct contact with the
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
and are involved in binding antigen, while the framework regions support the binding of the CDR to the
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
and aid in maintaining the overall structure of the four variable domains on the antibody.
To increase its stability, the framework region has less variability in its amino acid sequences compared to the CDR.
Function
The antibody has a three-dimensional structure with beta pleated sheet and alpha helices.
The antibody folds so the variable regions form three loops with the framework regions folded into one another and the CDR regions on the tips of each of these loops in direct contact with the antigen.
Residues are short amino acid sequences, residues of the framework region responsible for supporting the binding of the antigen to the antibody can be divided into two categories; residues that are in contact with the antigen and those not in contact with the antigen. Framework residues that come in contact with the antigen are a part of the antibody's binding site, and are located either close in sequence to the CDRs or in close proximity to the CDR when in the folded three dimensional structure.
Framework residues that do not come in contact with the antigen affect the binding indirectly by aiding in structural support for the CDR. This enables the CDR to take on the correct orientation and position so it is exposed on the surface of the chain ready to bind to an antigen.
The framework regions are highly conserved regions of the variable portion of the antibody. The evolutionary reason for the conservation of these regions is to support proper folding of the antibody allowing the CDR regions to be stabilized. Folding in FR leads to antibody structure flexibility or rigidity of the binding region of the antibody.
Mutations
Mutations in the framework regions of antibodies occur in cells by
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM div ...
and during affinity maturation of the antibody. In vitro, mutations of FR may occur by natural cause or by exposure to
mutagens
In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...
.
Recent studies of framework mutations imply that the framework region flexibility or rigidity could alter the specificity of the antibody to its intended epitope. While the framework region doesn't directly interact with antigen, its structure determines whether the CDRs can interact with antigen. If the CDR regions have high affinity for the epitope of antigen, it has been found to be more effective to have a more rigid framework region. When CDR does not have high affinity for antigen, mutations in the FR that create a more flexible structure may allow for higher affinity maturation.
Natural mutations in the variable region are typically due to
activation-induced cytidine deaminase
Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the ''AICDA'' gene. It creates mutations in DNA by deamination of cytosine base, which t ...
(AID). AID leads to deamination of cytosine to uracil in DNA and results in somatic hypermutation. This
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM div ...
allows for
immunoglobulin class switching
Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the ...
but also results in affinity maturation of the antibody. The CDR are the areas of the variable regions in contact with antigen and thus we see the most mutation in these regions. Although, the framework regions of the antibody are also mutated. Studies have shown that when the CDR is blocked from mutation and only the FR is mutated, certain mutations can lead to increased expression and thermostability of the antibody as a whole.
Antibody humanization is an example of beneficial genetic engineering in medicine today.
Humanized antibody refers to the creation of non-human antibody in vivo and in response to antigen, then the isolation and humanization of the framework and constant regions. It has been discovered that while these antibodies remain relatively intact upon transition, these modifications can also lead to decreased binding affinity in the humanized framework regions and result in improper folding in humans. This observation is believed to be due to the framework region's role in antibody structure.
also
*
Hypervariable region
A hypervariable region (HVR) is a location within nuclear DNA or the D-loop of mitochondrial DNA in which base pairs of nucleotides repeat (in the case of nuclear DNA) or have substitutions (in the case of mitochondrial DNA). Changes or repeat ...
*
Variable Region
References
{{Reflist
Proteins
Antibodies