what-when-how
In Depth Tutorials and Information
CHAPTER
15
FKBP10
(FKBP65 Protein), Osteogenesis
Imperfe
cta and Bruck Syn
drome
Deborah Krakow
1
and Yasemin Alanay
2
1
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA,
2
Acibadem University, Istanbul,
Turkey
INTRODUCTION
calcineurin, a Ca
2+
-activated calmodulin-dependent ser-
ine/threonine phosphatase, as well as the kinase activity
of mTOR homologs.
4
These activities then lead to inhibi-
tion of downstream signal transduction in T-lymphocyte
pathways and immunosuppression.
Since the initial identification of FKBP12, several
homologous FKBP family members have been identi-
ied. The FKBP family includes 16 proteins, ranging in
size from 12 to 135 kDa, and they are expressed among a
variety of tissues and subcellular compartments. Among
these, the FKBP class includes FKBP9, FKBP12, FKBP13,
FKBP25, FKBP52, FKBP54, FKBP60 and FKBP65.
5
FKBP
proteins are typically comprised of one to four FKBD
(PPIase) domains, usually followed by tetratricopeptide
repeat (TPR) domain, a C-terminal calmodulin-binding
domain and a trans-membrane motif. Beyond their roles
in suppression of T-cell activation with immunosuppres-
sive ligands, FKBP proteins are involved in a myriad
of cellular functions including protein folding, protein
stability, kinase activity, receptor signaling and protein
trafficking.
FKBP proteins were first identified in 1989 with the
isolation of FKBP12.
1
This highly conserved family of
proteins are ubiquitously expressed, highly conserved
and have been identified in a host of organisms including
bacteria, yeast,
Caenorhabditis elegans
and higher eukaryo-
types.
2
Accumulating evidence has shown that FKBP
proteins are involved in a variety of normal cellular pro-
cesses, as well as playing a role in cancer biology.
3
FKBP PROTEINS
The FK506-binding proteins (FKBPs) are highly con-
served proteins and belong to the immunophilin family.
2
Immunophilins are intracellular receptors of immuno-
suppressant drugs and these receptors were divided
into two classes based on their ability to bind immuno-
suppressant drugs; these drugs are used to treat auto-
immune disorders, as well as prevent organ rejection
after transplantation. Proteins that bind cyclosporine
A are referred to as cyclophilins. The prototype of the
FKBP family of proteins is FKBP12 and it has the mini-
mum domain structure necessary to be considered part
of the family. FKBP12 consists of a single FK506-binding
domain referred to as an FKBD domain. This domain
binds immunosuppressive drugs, such as FK506, cyclo-
sporine A and rapamycin, as well as having peptidyl-
prolyl cis/trans-isomerase activity (PPIase), the catalytic
property of peptidyl-prolyl cis-trans isomerization.
This binding of the FKBP domain with immunosup-
pressive drugs creates a complex that interferes with
FKBP10
/FKBP65 (PROTEIN
)
FKBP proteins exist in different compartments of the
cell and can be both membrane anchored and soluble
species. FKBP65 is one of the four FKBPs that are local-
ized to the endoplasmic reticulum (ER) and also include
FKBP13,
6
FKBP23
7
and FKBP60.
8
Since the ER is a major
site of protein folding, it has generally been accepted
that these FKBPs function as ER chaperones assisting in
protein folding and quality control. Because of the FKBP
