Fibrillin-1 is a mosaic protein mainly composed of 43 calcium binding epidermal 
growth factor-like (cbEGF) domains arranged as multiple, tandem repeats. 
Mutations within the fibrillin-1 gene cause Marfan syndrome (MFS), a heritable 
disease of connective tissue. More than 60% of MFS-causing mutations identified 
are localized to cbEGFs, emphasizing that the native properties of these domains 
are critical for fibrillin-1 function. The cbEGF12-13 domain pair is within the 
longest run of cbEGFs, and many mutations that cluster in this region are 
associated with severe, neonatal MFS. The NMR solution structure of 
Ca(2+)-loaded cbEGF12-13 exhibits a near-linear, rod-like arrangement of 
domains. This observation supports the hypothesis that all fibrillin-1 
(cb)EGF-cbEGF pairs, characterized by a single interdomain linker residue, 
possess this rod-like structure. The domain arrangement of cbEGF12-13 is 
stabilized by additional interdomain packing interactions to those observed for 
cbEGF32-33, which may help to explain the previously reported higher calcium 
binding affinity of cbEGF13. Based on this structure, a model of cbEGF11-15 that 
encompasses all known neonatal MFS missense mutations has highlighted a 
potential binding region. Backbone dynamics data confirm the extended structure 
of cbEGF12-13 and lend support to the hypothesis that a correlation exists 
between backbone flexibility and cbEGF domain calcium affinity. These results 
provide important insight into the potential consequences of MFS-associated 
mutations for the assembly and biomechanical properties of connective tissue 
microfibrils.