Download The FcRn Protein: From Mother to Fetus

The FcRn Protein: From Mother to Fetus
West Bend High School SMART Team:
Logan Riemer, Megan Petri, Christine Anhalt
1305 East Decorah Road, West Bend, WI 55095
Instructor: Trish Strohfeldt Mentor: Dr. Jason Bubier, The Jackson Laboratory 600 Main Street, Bar Harbor, ME 04609
Abstract
Fc Receptor Neonatal or FcRn is a protein in mammals by
which immunity is passed from mother to fetus before birth. FcRn
binds to Immunoglobin G (IgG) and transports IgG across the
placenta. FcRn is regulated by pH and is involved in the transport
of IgG through transport vesicles. FcRn is also important in its
control of the catabolism of IgG. It prevents degradation of IgG,
substantially increasing the half-life of IgG. Since FcRn has the
ability to increase the half-life of a protein, FcRn is a possible
therapeutic agent in treating some diseases.
Immunoglobulin: IgG
Of all the antibodies found circulating in the body, IgG is
the most common. IgG has the ability to cross the walls of blood
vessels, enter tissue fluids, and protect the body from bacteria,
viruses and toxins in the body. An Immunoglobulin consists of
four polypeptide chains; two heavy chains and two light chains
which together form a “Y” like shape. The variable regions on an
antibody allow it to bind to an antigen to help destroy or
inactivate the antigen.
Our model is that of a heterodimer consisting of
FcRn and beta-2-microglobulin. FcRn is seen in
magenta, light blue, and grey. The beta-2-microglobulin
is in dark green and purple. This model shows only part
of the entire heterodimer. The highlighted side chains in
blue (Asp-137), green (Glu-117), and yellow (Asp-132)
are those amino acids involved in the binding of FcRn to
IgG.
Mechanics of FcRn
•IgGs, which float in the blood stream, are important to mother and
additionally, the fetus to help it develop an immune response. IgGs must
be transported across the placenta since mother and fetus do not have
interconnecting blood vessels.
•IgGs are taken across the placenta by vesicles.
•A portion of the cell membrane folds inward to create a vesicle. The
pH of the vesicles is 6.0, lower than that of the blood and would induce
the degradation of IgG.
•FcRn binds to the Fc region of IgG to stabilize IgG
Once transferred, the FcRn is no longer needed and disassociates in the
higher pH of the fetal blood stream.
FcRn is shown here, in yellow and red, bound to
IgG, in blue and green. Two molecules of FcRn
are needed to transport one IgG.
FcRn
Therapeutic Uses of FcRn
The FcRn is very important in its ability to increase
antibody stability. FcRn may be able to help in the
treatment of diseases, such as lupus, in which the Fc region
of an IgG molecule is bound to a therapeutic protein. By
fusing the Fc domain to the protein, FcRn now has the
ability to bind to the therapeutic protein, thus increasing the
stability or half-life of the protein. IgG can last 22-23 days
in humans. This may be able to be applied to any disease
that is treated with a protein product.
Lupus
Lupus is an autoimmune disease. The function of a
normal immune system is to distinguish foreign invaders in
the body from self cells. When something goes wrong in
the system, it may begin to produce antibodies which
attack the body’s cells. This is considered an autoimmune
disorder. Antibodies to DNA (anti-DNA antibodies) are a
common feature of lupus. Patients receive injections of
proteins that inhibit the production of these anti-DNA
antibodies, thus stopping the DNA from being attacked.
By binding these injected proteins to the Fc region of IgG,
FcRn has the ability to stabilize the injected proteins,
decreasing the frequency with which the patient must be
injected.
Conclusion
FcRn is an important protein in the transfer of immunity to
the fetus from the mother. IgG molecules are not stable in low pH
environments and by binding to FcRn, the IgG molecules are more
stable while being transferred to the fetus.
This model is that of the entire
heteordimer, consisting of three FcRn
(blue) and three beta-2-microgobulin
(red). These models are from PDB file:
3FRU. These images were created using
RasMol and our model image was built
on a Z-corp printer.
FcRn is a naturally occurring protein in the body.
It is important in transferring immunity from the mother
to fetus. It also is important in its ability to increase the
half-life of a protein. This feature allows it to be used as
a potential therapeutic protein in diseases such as Lupus.
This graphic shows the process of the transportation of IgG by transcytosis from the mothers blood
stream through the placenta to the neonatal blood stream (Right). It also shows the recycling of
IgG (Left). The “Y” represents antibodies and FcRn is represented by small lines bound to the “Y”
antibodies.
Supported by the National Institutes of Health (NIH) – National Center for
Research Resources Science Education Partnership Award (NCRR(NCRR-SEPA)