1LMJ

NMR Study of the Fibrillin-1 cbEGF12-13 Pair of Ca2+ Binding Epidermal Growth Factor-like Domains

Summary for 1LMJ

• Entry DOI: 10.2210/pdb1lmj/pdb
• Related: 1EMO 1HJ7
• Descriptor: fibrillin 1, CALCIUM ION (2 entities in total)
• Functional Keywords: egf, calcium, microfibril, neonatal, marfan syndrome, connective tissue, extracellular matrix, structural protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix: P35555
• Total number of polymer chains: 1
• Total formula weight: 9589.90

Authors

Smallridge, R.S.,Whiteman, P.,Werner, J.M.,Campbell, I.D.,Handford, P.A.,Downing, A.K. (deposition date: 2002-05-02, release date: 2003-04-29, Last modification date: 2024-11-06)

Primary citation

Smallridge, R.S.,Whiteman, P.,Werner, J.M.,Campbell, I.D.,Handford, P.A.,Downing, A.K.
Solution Structure and Dynamics of a Calcium Binding Epidermal Growth Factor-like Domain Pair from the Neonatal Region of Human Fibrillin-1.
J.Biol.Chem., 278:12199-12206, 2003

PubMed Abstract: 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.

PubMed: 12511552
DOI: 10.1074/jbc.M208266200

Experimental method

SOLUTION NMR