B: A Prolyl Isomerase
Shante Jackson '13 and Irene McIntosh '13
Cyclophilin B (CyPB) is
peptidylprolyl isomerase (PPIase). PPIases activate
between the cis
conformations of amino acids during protein folding in the endoplasmic
reticulum (ER). This makes CyPB (and all other PPIases) a chaperone
protein, and one with a high affinity for isomerizing proline. CyPB
also has a high binding affinity for cyclosporine A (CsA), an
immunosuppresant that is used in the recovery of patiens who have
undergone organ trsnplant surgery and aides in reducing organ rejection.
is located in the ER of cells and binds to other ER
proteins to form a complex. A lectin chaperone such as calnexin
contains a proline rich "P-domain" that has negatively charged
aspartates and glutamates which interact with the positively charged
lysines on CyPB's P-domain-interacting site. The calnexin complex folds
N-glycosylated proteins by removing the N-glycan of the nitrogen
terminus of a protein.
cyclophilin family of proteins have immense structural
similarity, differing from A to D forms in their amino acid residues in
their domains surrounding a core.
has 8 antiparallel
beta sheets that form the beta barrel
by hairpin turns and hydrogen
between the sheets.
eyelet, or central opening, of this barrel is the hydrophobic core,
made up of proline,
and other nonpolar
are three alpha
helices that surround the
Two of these
serve to stabilize the barrel, while helix 1
part of the CsA binding pocket.
cyclophilin is in the calnexin complex,
it serves to isomerize the
amino acid proline. Proline
requires a high activation energy to convert from cis
conformation. Most amino acids prefer the trans
conformation when they bind to other amino acids because it's
sterically beneficial, but because of proline's ring structure it can
adopt the cis
conformation and remain stable.
in the p-domain
interacting area attach to the negative
glutamates on P-sites of other chaperone proteins in the ER.
Cyclosporine A Binding
A is a peptide initially harvested
from the fungus Tolypocladium
inlfatum and functions as an
immunosuppresant. It has a high
affinity for the CyB binding site, which is opposite the P-domain
binding site. When CsA is bound to CyPB, the PPIase activity of the
protein is blocked. CsA inhibits helper T-cells from being synthesized
when T-cell recepotors have been stimulated. The CsA enters the cell
and binds to its CyPB. The CyBP-CsA complex inhibits both the
enzyme responsible for activiating the creation of interleukins and the
one responsible for releasing them from the T-cell. The
capacity of the T-cell to start a signal chain against antibodies is
therefore reduced. How T-cells are
CsA binding pocket is hydrophobic and polar.
create one side of the pocket
located on the edge of
, is the main
binding site for CsA.
Forming the bottom and
opposite side of the pocket are various
residues and four beta
Cyclophilin B is found in most prokaryotes and eukaryotes.
All of the molecules in the cyclophilin family serve
important roles in various parts of the cell. Further
research of the cyclophilin-cyclosporine complex is needed to
understand it's possible use in medicinal fields.
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