UCS Proteins: Chaperones for Myosin and Co-Chaperones for Hsp90 - The Networking of Chaperones by Co-chaperones - page 139

have evolved (Gazda et al. 2013 ; Hellerschmied and Clausen 2014 ). Structural and
biochemical analyses suggested that CeUNC-45 (Gazda et al. 2013 ) forms tran-
sient linear protein structures (essentially short filaments) by oligomerization that is
mediated by a repeating TPR domain-neck region interaction (Gazda et al. 2013 ).
The tilting of both the TPR and UCS domains at specific angles relative to the rigid
central-neck domain enables two helices (7H2 and 8H2) in the neck region of one
molecule of CeUNC-45 to bind to two helices (TPR3B and kinked helix) in the TPR
domain of adjacent molecule in a defined array, and simultaneously allowing for
interaction with Hsp90/or Hsp70 and myosin motors (Fig. 7.3 ). The resulting multi-
meric scaffolds can thus serve as sites to recruit multiprotein chaperone complexes
that simultaneously assist in myosin folding and myofilament formation (Gazda
et al. 2013 ; Hellerschmied and Clausen 2014 ). Interestingly, it was observed that
the spacing (periodicity) of UNC-45 molecules in the so-called 'UNC-45 filaments'
may closely match the spacing of neighboring myosin heads in the thick filaments
under certain conditions (Gazda et al. 2013 ). Put together, these experimental ob-
servations provide strong evidence for the requirement for UCS proteins not only in
the folding of myosin heads but also in myofibrillar assembly (Myhre et al. 2014 )
and regulation of myosin-dependent processes. UCS proteins thus appear to be ac-
tive participants in sarcomere assembly (Myhre et al. 2014 ). The regulation of the
level of UNC-45 protein in muscle cells is important (Hoppe et al. 2004 ; Janiesch
et al. 2007 ; Landsverk et al. 2007 ). Overexpression of UNC-45 in muscle cells re-
sulted in increased myosin degradation and thus reduced or disorganized myofibrils
(Janiesch et al. 2007 ; Landsverk et al. 2007 ). The chaperoning activity of UNC-45
on myosin seems to be dependent on regulation by the ubiquitin/proteasome sys-
tem. A novel E3/E4-multiubiquitylation complex comprising of CDC-48, UFD-2
and CHN-1 proteins has been shown to link the turnover of both UNC-45 and myo-
sin to functional muscle formation (Hoppe et al. 2004 ; Janiesch et al. 2007 ). Similar
effects were observed in yeasts (Lord et al. 2008 ). From these studies, it is clear that,
apart from its involvement in myosin folding, myofibrillogenesis and functional
muscle formation, UNC-45 is important in muscle repair and perhaps aging (Hoppe
et al. 2004 ; Janiesch et al. 2007 ; Landsverk et al. 2007 ; Lord et al. 2008 ).
UNC-45 Proteins in Invertebrates
The unc-45 gene was originally identified in C. elegans through the recessive, ts
mutant allele, e286 (Epstein and Thomson 1974 ). C. elegans possesses only one
copy of the unc-45 gene. The e286 mutant worms are paralyzed, with disorganized
thick filaments in their muscles when grown at 25 ﾰC, but at the permissive tem-
perature of 15 ﾰC, the worms display phenotypes essentially similar to the wild-
type (Epstein and Thomson 1974 ). These phenotypes can be reversed by temper-
ature shifts in developing embryos and larvae but not in adult worms, implying
that UNC-45 possesses a function essential for proper myofilament arrays to form
(Epstein and Thomson 1974 ). Detailed genetic analysis revealed three additional