Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins - The Networking of Chaperones by Co-chaperones - page 82

Parasitic Diseases
Hsp70 and Hsp90 are considered drug targets for the treatment of infectious dis-
eases like malaria and trypanosomiasis. Hop is conserved across species, including
a number of parasitic organisms that cause disease in humans, such as Plasmodium
and Leishmania species. Hop from Leishmania donovani is expressed during the
amastigote stage (Joshi et al. 1993 ) which is important for adaption of the parasite to
the human host (Morales et al. 2010 ). Plasmodium falciparum Hop (PfHop) shares
a similar domain architecture with human Hop and the residues that are known
to be important in the interaction with Hsp70 or Hsp90 (Odunuga et al. 2003 ) are
conserved. However, despite the fact that chaperone and co-chaperone systems are
highly conserved, there is evidence that the proteins are sufficiently biochemically
different to be considered as putative drug targets. For example, the sequence of
plasmodial Hop proteins was different to those of yeast and mammals, despite the
structural conservation (Gitau et al. 2012 ). If these differences result in functional
changes, antimalarial compounds could be designed to selectively target distinct re-
gions of PfHop (Gitau et al. 2012 ). Similarly, deletion of specific residues in Leish-
mania donovani Hop blocked phosphorylation and led to parasite death (Morales
et al. 2010 ). If these residues are unique to the parasitic Hop, they may indeed be
targets for therapy. Furthermore, it may be relevant that the Hop interaction motif of
Hsp90 which is crucial for survival of the parasite is MEQVD in Leishmania spp.
instead of the MEEVD seen in the human host (Hombach et al. 2013 ).
Conclusion
While the exact biological function of Hop remains elusive, recent evidence from
knockout studies in mammals suggests that it is important in embryonic develop-
ment in this system at least. A role in development would be consistent with the
reported link between Hop and cancer characteristics. The biological function of
Hop will be system dependent, and while there are conserved features across spe-
cies, the sequence and domain variations suggest that it could have been recruited
by evolution for a number of different biological roles. The diverse functions of
Hop in mammalian cells, suggests that at least two major isoforms may exist, one
intracellular and the other extracellular, although direct evidence for this has yet
to be presented. Identification and elucidation of the molecular basis for these iso-
forms and their seemingly divergent cellular functions is an exciting area for future
research. How has this dynamic scaffold protein been functionally adapted to such
different roles and processes? A deeper structural and functional understanding of
these Hop isoforms will assist research on the role of Hop in cancer. The intracellu-
lar isoform appears to be involved in processes important for successful metastasis
while the extracellular isoform appear to enhance proliferation of cancer cells. The
identification of small molecules that can specifically disrupt Hop and its partner
protein interactions are starting to emerge. These Hop modulators represent novel