The Evolution and Function of Co-Chaperones in Mitochondria - The Networking of Chaperones by Co-chaperones - page 208

interacts with nucleotide and does not need a nucleotide exchange factor, but Ssq1,
like Ssc1, interacts strongly with nucleotides and requires Mge1 as a nucleotide ex-
change factor (Dutkiewicz et al. 2003 ). This sharing of a nucleotide exchange factor
between two Hsp70s in the same cellular compartment is unique to mitochondria
(Schmidt et al. 2001 ). Disruption of Ssq1 is less detrimental to cells than depletion
of Jac1, and it can be partially complemented by over-expression of Ssc1 (Schilke
et al. 1996 ). Ssq1 is absent from most eukaryotic organisms, and is likely a special-
ized isoform of Ssc1 devoted to FeS cluster assembly. The J domain of Jac1 in yeast
is shorter than that in organisms that do not have Ssq1 (Pukszta et al. 2010 ). When
expressed in yeast, these Jac1 proteins can complement the loss of Ssq1 function
to a greater degree than yeast Jac1, suggesting that they recruit Ssc1 to perform the
FeS cluster assembly role. Consistent with these findings is the observation that
Ssc1 can interact with Jac1 in vitro , but to a lesser extent than Ssq1 (Schilke et al.
2006 ). These observations strongly suggest that Hsp70 function is essential for FeS
cluster assembly.
Zim17, a Unique Regulator of Hsp70
Hsp70 chaperones require various co-chaperone regulators to carry out their cel-
lular role. Since the discovery of bacterial Hsp70 system, until recently, the only
known regulators of mitochondrial Hsp70 were members of the J protein family or
the nucleotide exchange factors. The first Hsp70 co-chaperone identified that does
not belong to either group was the Hsp70/Hsp90 organizing protein Hop. Recently,
a novel protein essential for function of Hsp70s has been described in mitochondria
(Burri et al. 2004 ). The 17 kD peripheral membrane protein, Zim17/Tim15/Hep1,
has an essential zinc finger domain homologous to that of bacterial DnaJ. Loss of
Zim17 function leads to aggregation of Ssc1 and Ssq1, disruption of mitochondrial
protein import, loss of function of FeS cluster proteins and aberrant mitochondrial
morphology (Sanjuan Szklarz et al. 2005 ; Lewrenz et al. 2013 ). Decrease in FeS
cluster biosynthesis due to Zim17 disruption also results in the increased rate of
nuclear genome recombination and alterations in ribosome biogenesis (Diaz de la
Loza Mdel et al. 2011 ).
Since Pam18 is a type III J protein, Zim17 was hypothesized to be the substrate-
binding domain of a “fractured” co-chaperone, with the coordinated action of the
two proteins resembling that of a type I J protein (Burri et al. 2004 ). Initially, it was
suggest Zim17 might play a role in protein import by binding precursors emerging
from the TIM23 pore and mediating their interaction with Ssc1 (Burri et al. 2004 ;
Yamamoto et al. 2005 ). Subsequent studies have established that aggregation of
Hsp70s (and to some extent Pam16) is the first effect of Zim17 depletion, and that
other disruptions of mitochondrial processes result from the loss of Hsp70 func-
tion (Sichting et al. 2005 ; Sanjuan Szklarz et al. 2005 ). Most recent work, utilizing
temperature sensitive mutants of Zim17, revealed that Zim17 might play a more