Biomedical Engineering Reference
In-Depth Information
folded region becomes more stably folded.
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However, the mutant IkBa was
significantly less capable of stripping NFkB from DNA.
71
5.4.2 Binding-Induced Molten Globule-Like States
The reverse behavior, where binding of a partner appears to loosen the
structure of a protein that is well folded in isolation, occurs when the p53 DNA
binding domain interacts with the chaperone Hsp90. NMR, fluorescence and
H/D exchange experiments all point to the formation of a loosened and flexible
state of the p53 DNA-binding domain (DBD) in the presence of Hsp90.
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The
interaction of the p53 DBD appears to be essential for the stability of p53 at
physiological temperatures towards irreversible thermal inactivation.
73
Yet it
also appears that the p53 DBD is, in a sense, destabilised by the presence of
Hsp90 and its domains, since it appears to form a molten globule-like state.
72
The explanation for these apparent contradictions may lie in the dynamic
nature of the primary interaction between the Hsp90 and its client: the
interactions of Hsp90 and client proteins in vivo are modulated by other
protein factors, including other chaperones such as Hsp70 and Hsp40, co-
chaperones such as p23 and Aha1 and small molecules such as ATP. Also, the
function of a chaperone such as Hsp90 may not be to stabilise the folds of
proteins, but rather to hold them in states that are conducive to their
subsequent function. For example, the nuclear hormone receptor ligand
binding domains are prominent clients of Hsp90, and are well known to
require Hsp90 in order to remain in a stable hormone-receptive state in the
resting cytoplasm.
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The dynamic and non-specific nature of the interaction
may also provide a rationale for the range of structures and sequences in the
client proteins of Hsp90.
5.5 Functional Disorder in Folded States
Motion is inherent in all biomolecules, and is frequently associated with or
required for function. For example, the presence of polypeptide chain
dynamics in enzymes is frequently important for catalysis
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and may even
influence the chemical step in surprising ways.
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Motion is also important for
molecular systems whose primary function is binding, for example in antigen-
antibody union
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and in the binding of intrinsically disordered activation
domains to their partners (see above).
5.5.1
Sequence Specificity of Zinc-Finger Proteins
One case where disorder is required for specificity, largely independent of
binding affinity, is in the interactions of zinc-finger proteins with nucleic acids.
Zinc-finger protein genes are widely distributed in published genomes,
identified by patterns of potential zinc-binding side-chains such as cysteine
and histidine. These proteins are classified according to the identity of the
