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J. Biol. Chem., Vol. 276, Issue 20, 17156-17162, May 18, 2001
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From the Divisions of Human fibrillin-1, an extracellular matrix
glycoprotein, has a modular organization that includes 43 calcium-binding epidermal growth factor-like (cbEGF) domains arranged
as multiple tandem repeats. A missense mutation that changes a highly
conserved glycine to serine (G1127S) has been identified in cbEGF13,
which results in a variant of Marfan syndrome, a connective tissue
disease. Previous experiments on isolated cbEGF13 and a cbEGF13-14 pair indicated that the G1127S mutation caused defective folding of cbEGF13
but not cbEGF14. We have used limited proteolysis methods and
two-dimensional NMR spectroscopy to identify the structural consequences of this mutation in a covalently linked cbEGF12-13 pair
and a cbEGF12-14 triple domain construct. Protease digestion studies of
the cbEGF12-13 G1127S mutant pair indicated that both cbEGF12 and 13 retained similar calcium binding properties and thus tertiary structure
to the normal domain pair, because all identified cleavage sites showed
calcium-dependent protection from proteolysis. However,
small changes in the conformation of cbEGF13 G1127S, revealed by
the presence of a new protease-sensitive site and comparative
two-dimensional NOESY data, suggested that the fold of the mutant
domain was not identical to the wild-type, but was native-like.
Additional cleavage sites identified in cbEGF12-14 G1127S indicated
further subtle changes within the mutant domain but not the flanking
domains. We have concluded the following in this study. (i) Covalent
linkage of cbEGF12 preserves the native-like fold of cbEGF13 G1127S and
(ii) conformational effects introduced by G1127S are localized to
cbEGF13. This study demonstrates that missense mutations in
fibrillin-1 cbEGF domains can cause short range structural effects in
addition to long range effects previously observed with a E1073K
mutation in cbEGF12.
A G1127S Change in Calcium-binding Epidermal Growth
Factor-like Domain 13 of Human Fibrillin-1 Causes Short Range
Conformational Effects*
,
,,,¶
Molecular and Cellular
Biochemistry and § Structural Biology, Department of
Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU,
United Kingdom
*
This work was supported in part by the Wellcome
Trust.The costs of publication of this
article were defrayed in part by the payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by the Medical Research Council and St. Johns
College, Oxford.
**
A Wellcome Trust Senior Fellow.
To whom correspondence should be addressed. Tel.: 44 0 1865 285347; Fax: 44 0 1865 275259; E-mail: penny@bioch.ox.ac.uk.
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