protein folding

Barbara A. Seaton seaton at MED-XTAL.BU.EDU
Tue Apr 19 19:19:43 EST 1994

> 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

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

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