Transcript From the Cradle to the grave: molecular chaperones that may

From the Cradle to the grave:
molecular chaperones that may
choose between folding and
degradation
By: Erica Zakhem
Proteins
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The function of a protein is determined by the
3D structure of the Amino Acid chain
This 3D structure is produced after translation
Proteins are constantly under threat of
unfolding due to chemical and cellular stress
Hydrogen bonds may be disrupted by change in
temperature and varying pH levels
Protein structure
Protein structure and quality is mediated by two
systems
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Molecular chaperones
Energy-dependent proteases
Molecular chaperones
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They aid in the binding of non-native proteins,
and inhibit protein aggregation
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Work with regulatory co-chaperones to
facilitate the protein folding process
Energy-dependent proteases
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Eliminate proteins that do not fold according to
their native 3D structure
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Misfolded proteins are sent to the cell’s
degradation machinery for destruction
Hsp70 and Hsp90
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The major chaperones found in mammals are
the Heat shock proteins 70 and 90
Hsp70 is involved in the folding of newly
synthesized proteins, and in the protection of
proteins during cellular stress and protein
trafficking
Hsp90 functioning is restricted, but it plays a
role in stress protection
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Both these types of chaperones are associated
with non-native protein substrates through the
hydrophobic portions in the native 3D structure
They control conformational regulation of
proteins involved in signal transduction, cell
proliferation, and apoptosis
They cooperate with the degradation machinery
in the cell
Hsp70 and Hsp90 have been shown to require
several co-chaperones in order to act
Co-chaperones
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They can take either one of two options when
regulating chaperone functioning
They can regulate the ATPase cycle of the
chaperone, thus influencing its affinity for the
protein substrates
Or they can recruit the chaperones to specific
proteins or protein complexes
Many co-chaperones exhibit both chaperonebinding and chaperone-regulating motifs
Chaperone-binding motifs
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Chaperone-binding motifs found in Hsp70 and
Hsp90 co-chaperones consist of a tandem
arrangement of three degenerate 34 amino acid
repeats-tetratricopeptide repeats, TPRs
The Hsp70/Hsp90 organizing protein Hop
contains multiple TPRs which allow it to bind to
Hsp70 and Hsp90, and to promote the
regulation of signal transduction pathways
Ubiquitin/proteosome system
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Major degradation pathway in eukaryotic cells
Proteins that are to be degraded are labeled with
a multi-ubiquitin chain
The proteins are then taken to 26S proteosome
which consists of proteases which degrade the
proteins.
Ubiquitylation is mediated by an enzyme
complex comprising of E1, E2 and E3
Carboxyl terminus of Hsp70
Interacting Protein-CHIP
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CHIP is a co-chaperone that interacts with Hsc70,
and it accelerates ubiquitin-dependent
degradation of chaperone substrates
The N-terminal contains three tandem TPRs
adjacent to a highly charged α-helix which form a
chaperone adaptor
The C-terminal contains a U-box comprising of a
ubiquitin activator (E1), a ubiquitin conjugating
enzyme (E2) and a ubiquitin ligase enzyme (E3)
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The structure of CHIP enables the cochaperone to link molecular chaperones to the
degradation machinery
CHIP targets substrates to the
ubiquitin/proteasome system and controls the
balance between protein folding and protein
degradation
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CHIP plays an integral role in the ubiqutin ligase
complex
Its ability to recognize non-native proteins and
specific proteins allows it to select substrates for
CHIP-mediated ubiquitylation
Association with Hsp70 and Hsp90 promotes
the ubiquitylation process of various substrates
Chaperone machines
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Upon association with CHIP chaperones Hsp70
and Hsp90 are turned into degradation factors
Regulation of protein quality occurs when CHIP
occupies co-chaperone sites on Hsp70 and
Hsp90 it competes with other co-chaperones
Hop is a co-chaperone that is a CHIP antagonist
Like CHIP, Hop associates with Hsp70 via the
TPR adapter
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As opposed to CHIP,
Hop assists in
chaperone-mediated
protein folding
Competing cochaperones determine
whether a chaperone
machine is involved in
protein folding or
protein degradation
BAG-1
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The Hsp70 co-chaperone BAG-1 acts as a link
between molecular chaperones and the
ubiquitin/proteasome system
This co-chaperone uses its ubiquitin domain for
binding to the proteasome, which promotes
association between Hsp70 and the proteolytic
complex
Increased BAG-1 levels is insufficient to
promote degradation
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A co-chaperone complex that includes both
CHIP and BAG-1 has been shown to regulate
proteasomal sorting of chaperone substrates
CHIP binds to the C-terminal while BAG-1
binds to the N-terminal of the chaperone
BAG-1 competes with Hip, which is a foldingstimulating co0chaperone in the binding to the
ATPase of Hsp70
Again, this illustrates that competing factors
determine the function of molecular chaperones
Hip and BAG-1 compete for binding to the
ATPase, while CHIP and Hop compete for
association with the C-terminal
Conclusions
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Hsp70 and Hsp90 interact with many cochaperones that determine their fate
Co-chaperones have been used elucidate the
roles of chaperones in protein folding and
degradation
Our knowledge of chaperones and cochaperone mechanisms are still limited