protein folding

Richard Engh engh at nmrvex.biochem.mpg.de
Tue Apr 19 05:05:29 EST 1994


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Regarding differences between nmr, X-ray, and
physiological structures:

1)  We've seen one case where a relatively small cysteine
proteinase inhibitor with a flexible, partially undefined,
partially helical structure in the crystal adopts a well-
defined but completely different structure in solution.  It
looks like this is caused by crystal contacts:
--Engh, et al., J. Mol. Biol. 234, 1060-69, 1993.
--Dieckmann et al., J. Mol. Biol. 234, 1048-1059, 1993.
This variation occurs in a region with no known function,
although it is relatively conserved.  At the site of
closest contact with a protease, however, the solution structure
is more like the structure of the inhibitor-enzyme complex,
as seen in a crystal structure:
--Stubbs et al., EMBO J. 9, 1939-1947, 1990
There are a few references in Engh et al. to other comparisons,
like complement proteins and the trp repressor.

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.

3)  To some extent, the very high agreement in general between X-ray
and NMR structures may be influenced by the fact that rigid proteins
crystallize better than flexible ones; so the comparisons deal mostly
with rigid proteins.  There has been a lot of attention given to  the
serpin family of proteinase inhibitors lately; these must be flexible
for their activity.  A literature search with "serpin" as
keyword should give a cornucopia of hits.  Some self-citation:
-Schulze et al., FEBS Lett, in press
-Engh et al., Behring Inst. Mitt. 93, 41-62, 1993
-Schulze et al., Biochemitsry 31, 7560/7565, 1992
See also:
-Nature 368, 7-April-1994, p 570 for commentary and other references.






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