p23 and Aha1 - The Networking of Chaperones by Co-chaperones - page 114

(Wandinger et al. 2008 ). Most Hsp90 cochaperones are TPR-proteins and therefore
interact with the C-terminal MEEVD-motif of Hsp90. The only exception here is
the cochaperone Sgt1, which interacts despite the presence of a TPR-domain with
the N-terminal domain of Hsp90. In contrast to the TPR-cochaperones, the number
of known non-TPR cochaperones is much smaller. p23 and Aha1 are two prominent
examples of non-TPR proteins.
The Cochaperone p23
Discovery and Occurrence
p23 is a highly acidic protein which was first identified in a complex with Hsp90
and the avian progesterone receptor (Johnson et al. 1994 ). It was named, like sev-
eral other chaperones, according to its molecular weight and is hence the small-
est cochaperone of the Hsp90 machinery. p23's existence is however not confined
to Hsp90 complexes, as it fulfills several Hsp90-independent functions in the cell
(Echtenkamp et al. 2011 ). The identification of p23 from yeast to man suggests
that p23 is a conserved protein (Johnson et al. 1994 ). Subsequent studies and the
increasing existence of genome sequences allowed the identification of p23-like
proteins in plants (Krishna and Gloor 2001 ; Cha et al. 2009 ; Zhang et al. 2010 ),
which may differ in their effects on Hsp90. p23 is expressed in all mammalian
tissues with the exception of striated muscles, where its homologue tsp23 is ex-
pressed instead (Freeman et al. 2000 ; Grad et al. 2006 ). Within the eukaryotic cell,
the localization of this small protein is still not completely clear. The fact that the
p23 sequence does not contain any known localization signals, defines the protein
as cytoplasmatic. Nevertheless, it was also found in the nucleus (Picard 2006b ; Ge
et al. 2011 ), which is in agreement with newly identified functions of p23 in this
compartment (Echtenkamp et al. 2011 ; Zelin et al. 2012 ). Questions like how p23
reaches these destinations and what portions of cellular p23 are localized in these
cellular compartments are still elusive. Moreover, p23-Hsp90-complexes were also
found outside the cell, implying an extracellular, not yet completely understood
function of p23 (Eustace and Jay 2004 ; Sims et al. 2011 ).
Structure
First structural investigations of p23 based on protease sensitivity and CD-
spectroscopy suggested a ʲ-sheet fold with an unstructured C-terminal region
(Weikl et al. 1999 ). This view was confirmed by crystal structures of human and
yeast p23 (Weaver et al. 2000 ; Ali et al. 2006 ) as well as NMR studies (Martinez-
Yamout et al. 2006 ). According to atomic structures, p23 can be divided in a sta-
bly folded N-terminal domain, organized as a seven stranded ʲ-sandwich and a