NMR analysis of cbEGF domains gives new insights into the structural consequences of a P1148A substitution in fibrillin-1 |
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Authors: | Whiteman P; Downing AK; Handford PA |
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Affiliation: | Sir William Dunn School of Pathology, University of Oxford, UK. |
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Abstract: | Fibrillin-1 is a modular glycoprotein and a major component of the 10- 12
nm microfibrils of the extracellular matrix. Mutations in the fibrillin-1
(FBN 1) gene result in the connective tissue disease the Marfan syndrome
(MFS) and related disorders. The calcium binding EGF- like (cbEGF) domain
is the predominant structural motif of the protein and >70% of mutations
leading to MFS disrupt this domain. A missense mutation which changes a
proline to alanine (P1148A) in cbEGF domain 13 has been associated with a
number of fibrillin disorders including MFS and Shprintzen-Goldberg
syndrome. However, it has also been described as a polymorphism. In this
study comparative NMR analyses on wild-type and mutant forms of
covalently-linked fibrillin cbEGF domain pairs have been performed to
investigate the structural consequences of this substitution. A comparison
of the two-dimensional NOESY spectra of the wild-type and mutant forms of
cbEGF domains 12 & 13 and cbEGF domains 13 & 14 indicated that the
proline to alanine amino acid change does not introduce a significant
structural defect into cbEGF domain 13 or the adjacent domains and most
likely represents a polymorphism. These results demonstrate how, in the
case of a protein with a well defined domain organisation such as
fibrillin-1, comparative NMR analyses can be used to substantiate genetic
evidence for the polymorphic status of an amino acid.
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