Biomedical Engineering Reference
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contains four zinc fingers that interact with a specific duplex DNA sequence.
Alternative splicing leads to the insertion of a tripeptide, Lys-Thr-Ser into the
linker between fingers 3 and 4. 87 This insertion disrupts the 'snap-lock' of the
linker sequence between fingers 3 and 4, abrogating binding of finger 4 in the
+KTS isoform of the protein. This is shown by the relaxation behavior of the
four-finger protein in the presence and absence of DNA: both the 1 H- 15 N
NOE and the t m values measured for the alternatively spliced proteins show
that finger 4 exists independently of the rest of the complex in the +KTS
isoform 83 (Figure 5.9). This example provides an experimental verification of
the principle that alternative splicing, which provides conformational and
functional diversity in proteins, operates via the variation of the intrinsic
disorder of operative segments of the protein.
5.6 Conclusions
The foregoing provides only a small slice of the available information
concerning functional proteins that are disordered or incompletely structured.
More information is appearing every day. Once we accept that proteins do not
have to be well folded to have important physiological functions, the
appearance of studies on proteins that previously would have remained
unexamined as 'too difficult' or 'not relevant' will become more common. In
the process we will discover new insights into the mechanisms of metabolic
control. This promises to be a fertile new field. NMR has been at the forefront
of these studies so far. Structural insights gained in solution on these systems
must necessarily be incomplete and low resolution, but it remains the best
information we have at present. High-resolution structures are not possible for
structural ensembles at present: crystallography and even solution structure
determination is impossible, and a valid solution to this problem may neverbe
found. Nevertheless, we can and do study these systems by NMR and other
solution methods, and use the data to obtain important new information.
References
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