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Vol. 10, Issue 7, 2101-2117, July 1999
Department of Biology, Temple University, Philadelphia,
Pennsylvania 19122
The Drosophila melanogaster HSC3 and
HSC4 genes encode Hsc70 proteins homologous to the
mammalian endoplasmic reticulum (ER) protein BiP and the cytoplasmic
clathrin uncoating ATPase, respectively. These proteins possess ATP
binding/hydrolysis activities that mediate their ability to aid in
protein folding by coordinating the sequential binding and release of
misfolded proteins. To investigate the roles of HSC3
(Hsc3p) and HSC4 (Hsc4p) proteins during development, GAL4-targeted gene expression was used to analyze the effects of
producing dominant negatively acting Hsc3p (D231S, K97S) and Hsc4p
(D206S, K71S) proteins, containing single amino acid substitutions in
their ATP-binding domains, in specific tissues of
Drosophila throughout development. We show that the
production of each mutant protein results in lethality over a range of
developmental stages, depending on the levels of protein produced and
which tissues are targeted. We demonstrate that the functions of both
Hsc3p and Hsc4p are required for proper tissue establishment and
maintenance. Production of mutant Hsc4p, but not Hsc3p, results in
induction of the stress-inducible Hsp70 at normal temperatures.
Evidence is presented that lethality is caused by tissue-specific
defects that result from a global accumulation of misfolded protein
caused by lack of functional Hsc70. We show that both mutant Hsc3ps are defective in ATP-induced substrate release, although Hsc3p(D231S) does
undergo an ATP-induced conformational change. We believe that the amino
acid substitutions in Hsc3p interfere with the structural coupling of
ATP binding to substrate release, and this defect is the basis for the
mutant proteins' dominant negative effects in vivo.
Corresponding author. E-mail address:
palter{at}astro.ocis.temple.edu.
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