protein folding

David Rose drose at pip.oci.utoronto.ca
Wed Apr 20 08:25:33 EST 1994


In article <Pine.3.07.9404191955.B828-c100000 at MED-XTAL.BU.EDU> seaton at MED-XTAL.BU.EDU ("Barbara A. Seaton") writes:
>
>> On 19 Apr 1994, Richard Engh wrote:
>
>> Regarding differences between nmr, X-ray, and
>> physiological structures:
>
>> 2)  I don't have the reference at hand, but the annexins, a class
>> of membrane binding proteins, possess either three or four calcium
>> binding sites, depending on the crystal contacts.  Presumably the
>> fourth requires hydrophobic crystal contacts in order to adopt
>> a calcium binding conformation.  This may parallel events during
>> membrane attachment; if so, the 'disturbing' crystal contacts actually
>> create a physiologically conformation.
>
>We did observe in our annexin V structure that the fourth domain both
>binds calcium and exhibits a markedly different conformation from similar
>structures that lack bound calcium in that domain (Concha et al., Science
>261, 1321, 1993). The larger picture is actually rather complicated.
>Spectroscopic studies (by Paul Meers) of the lone tryptophan in that loop
>have shown that that particular conformation can be induced by high
>calcium alone -- in solution. It would seem that the conformation must
>first exist before a crystal lattice can build itself around it. If the
>calcium concentration is lowered after these crystals form, they quickly
>dissolve. It seems that high calcium is actually the most critical
>parameter for this crystal form. 
>
>However, hydrophobic contacts are evident in the crystals at the lattice
>points involving the tryptophan in the 4th calcium binding site. These
>have been hypothesized to stabilize (in the crystal) this more "open"
>conformation that is triggered by calcium binding, either through
>exploitation of "normal" protein-protein contacts or by serendipitously
>mimicking the nearby lipid bilayer. The significance of these observations
>has not been firmly established. In any event, it will probably be seen
>that the crystal utilizes, rather than merely stabilizes, this particular
>conformation. 
>
>The tendency of proteins to exploit physiologically relevant conformations
>or protein-protein interactions in forming a crystal lattice can, in
>many cases, give important clues about macromolecular assembly processes.
>I personally would like to hear from others out there who have made
>similar observations...
>
>Barbara Seaton
>seaton at medxtal.bu.edu
>
>
>

 The MHC structure from Wiley last year springs to mind where an unexpected
dimerization was noted in the crystal packing and was proposed to reflect
a physiological dimerization in T-cell activation. I suppose just about any
enzyme that works as a multimer where monomers pack together in the crystal
to form the active enzyme (eg, TIM) might be looked at in this way, too.

David




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