Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 52

FKBP6 deletion in this syndrome is not clear since several contiguous genes on
chromosome 11, including genes for elastin and LIM-Kinase 1, are also deleted
in these patients and clearly contribute to some phenotypic aspects.
FKBP38
FKBP38 (gene name FKBP8 ) contains a glutamate-rich domain, FK domain, three
TPR domains, and a calmodulin-binding motif. FKBP38 is ubiquitously expressed
in all tissues, with high expression in neuronal tissues. Among the FKBP family,
FKBP38 is novel in several respects, including a unique C-terminal transmembrane
anchor domain, used to localize FKBP38 to both the mitochondrial and ER mem-
branes. Although FKBP38 contains a PPIase domain, PPIase activity is regulated.
The structure of the PPIase domain is similar to the prototypical family member,
FKBP12; however, there are important differences in the three-dimensional struc-
ture of the loop and the binding pocket of the active site (Maestre-Martinez et al.
2006 ; Kay 1996 ). The loss of several aromatic residues in the active site leads to
lower PPIase activity, even upon activation, and low affinity for FK506 (Maestre-
Martinez et al. 2006 ; Edlich et al. 2006 ). FKBP38 PPIase activation is dependent
on the calmodulin-binding domain and calmodulin/Ca 2+ binding stimulates PPIase
activity (Edlich et al. 2005 ; Edlich et al. 2007b ; Maestre-Martinez et al. 2010 ).
FKBP38 participates in a number of cellular processes involving protein folding
and trafficking, apoptosis, neural tube formation, CFTR trafficking, and viral repli-
cation (Edlich and Lucke 2011 ; Banasavadi-Siddegowda et al. 2011 ). FKBP38 in-
teracts with the anti-apoptotic proteins Bcl-2 in regulating apoptosis and appears to
have both pro- and anti-apoptotic activity that is likely tissue specific (Shirane and
Nakayama 2004 ). In general, FKBP38 anti-apoptotic activity appears to regulate
apoptosis by transporting Bcl-2 to the mitochondrial membrane stabilizing Bcl-2
and inhibiting apoptosis (Shirane and Nakayama 2004 ). Two mechanisms on how
FKBP38 protects Bcl-2 from degradation have been explored. One involves the
interaction between FKBP38 and a caspase cleavage site located within Bcl-2 (Choi
et al. 2010 ). When FKBP38 is associated with Bcl-2 access to the caspase cleavage
site may be blocked, preventing caspase-mediated Bcl-2 degradation (Choi et al.
2010 ). The second mechanism is through an interaction between the S4 subunit of
the 19S proteasome complex, thereby regulating proteasome activity. However, in
neuroblastoma cells the active FKBP38/calmodulin/Ca 2+ complex has a pro-apop-
totic affect by interfering with the ability of Bcl-2 to interact with and block pro-
apoptotic proteins (Edlich et al. 2005 ). In this case, an interaction between Hsp90
and the FKB38/calmodulin/Ca 2+ complex interferes with FKP38 pro-apoptotic ac-
tivity, which could impede apoptosis (Edlich et al. 2007a ).
FKBP38 is also implicated in the regulation of mTOR signaling through an in-
teraction with Rheb (Rosner et al. 2003 ). mTOR regulates a wide range of cellular
processes, including cell cycle and cell growth, in response to various conditions,