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2014 ; 289
(40
): 27470-80
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Biochemical characterization of mutants in chaperonin proteins CCT4 and CCT5
associated with hereditary sensory neuropathy
#MMPMID25124038
Sergeeva OA
; Tran MT
; Haase-Pettingell C
; King JA
J Biol Chem
2014[Oct]; 289
(40
): 27470-80
PMID25124038
show ga
Hereditary sensory neuropathies are a class of disorders marked by degeneration
of the nerve fibers in the sensory periphery neurons. Recently, two mutations
were identified in the subunits of the eukaryotic cytosolic chaperonin TRiC, a
protein machine responsible for folding actin and tubulin in the cell. C450Y CCT4
was identified in a stock of Sprague-Dawley rats, whereas H147R CCT5 was found in
a human Moroccan family. As with many genetically identified mutations associated
with neuropathies, the underlying molecular basis of the mutants was not defined.
We investigated the biochemical properties of these mutants using an expression
system in Escherichia coli that produces homo-oligomeric rings of CCT4 and CCT5.
Full-length versions of both mutant protein chains were expressed in E. coli at
levels approaching that of the WT chains. Sucrose gradient centrifugation
revealed chaperonin-sized complexes of both WT and mutant chaperonins, but with
reduced recovery of C450Y CCT4 soluble subunits. Electron microscopy of
negatively stained samples of C450Y CCT4 revealed few ring-shaped species,
whereas WT CCT4, H147R CCT5, and WT CCT5 revealed similar ring structures. CCT5
complexes were assayed for their ability to suppress aggregation of and refold
the model substrate ?d-crystallin, suppress aggregation of mutant huntingtin, and
refold the physiological substrate ?-actin in vitro. H147R CCT5 was not as
efficient in chaperoning these substrates as WT CCT5. The subtle effects of these
mutations are consistent with the homozygous disease phenotype, in which most
functions are carried out during development and adulthood, but some selective
function is lost or reduced.
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