Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins - The Networking of Chaperones by Co-chaperones - page 71

et al. 2008 ). Recently, studies using astrocyte cell lines identified PIAS1 (protein
inhibitor of activated STAT1) as a nuclear retention factor for Hop (Soares et al.
2013 ). The mechanism by which Hop is transported to the plasma membrane and
extracellular environment is currently undefined, although there is evidence for ex-
port of Hop from mouse astrocytes in exosomes derived from multivesicular bodies
(Hajj et al. 2013 ).
Structure of Hop
Structurally, Hop is composed of repeating units of two different types of domain,
namely the tetratricopeptide repeat (TPR) motif and the aspartate-proline (DP) motif
domains. Hop contains three TPR domains (designated TPR1, TPR2A and TPR2B)
each of which is formed from three TPR motifs. There are two DP domains, the
DP1 and DP2 domains, which are positioned between TPR1 and TPR2A and C
terminal to TPR2B of Hop, respectively. The TPR domains of Hop are amongst
the best characterised (Scheufler et al. 2000 ; Brinker et al. 2002 ; Odunuga et al.
2003 ; Odunuga et al. 2004 ; Onuoha et al. 2008 ). The TPR motif is a protein-protein
interaction module that is found in a range of proteins, which are involved in di-
verse cellular processes, from transcription to protein degradation (Allan and Rata-
jczak 2011 ). The structure of the TPR domain consists of modules of anti-parallel
α-helices arranged in tandem creating an amphipathic groove which is the main site
of protein-protein interactions (Allan and Ratajczak 2011 ). In co-chaperones, TPR
domains mediate the interaction with Hsp70 or Hsp90 by binding to the conserved
C terminal EEVD motif of the cytosolic isoforms of the chaperones. Among co-
chaperones of Hsp70 and Hsp90, the TPR motif is not unique to Hop, and is also
found in CHIP and HIP.
Mutational studies in both yeast and murine systems have demonstrated that
the TPR domains of Hop display different affinity for the Hsp70 and Hsp90 chap-
erones (Odunuga et al. 2003 ; Song and Masison 2005 ). Mutations in TPR1 but
not TPR2AB impair Hsp70 binding, while the converse is true for Hsp90 bind-
ing. The ability of Hop to discriminate between Hsp70 and Hsp90 EEVD motifs
is mediated by specific TPR residues which interact with residues immediately
upstream of the EEVD (GPTIEEVD in the case of Hsp70 and MEEVD in the
case of Hsp90) (Odunuga et al. 2003 ; Carrigan et al. 2004 ). Hop is therefore dif-
ferentiated from other TPR-containing co-chaperones in that its TPR domains
can discriminate between Hsp70 and Hsp90 (Odunuga et al. 2003 ; Carrigan et al.
2004 ). Conserved residues in the TPR domains form a carboxylate clamp with
the C-terminal EEVD motif in the chaperones. Adjacent residues in TPR1 and
TPR2A promote high affinity binding to either the GPTIEEVD peptide of Hsp70
or the MEEVD peptide of Hsp90, respectively (Scheufler et al. 2000 ; Brinker
et al. 2002 ; Odunuga et al. 2003 ).
More recent evidence proposes a model in which Hop binding to Hsp90 is not
restricted only to the C-terminal EEVD motif. Hop also appears to interact with N