Mini reviewFibrillin: from domain structure to supramolecular assembly
Section snippets
Molecular structure of the fibrillins
Initial cloning and sequencing of 6.9 kb of the 3′ translated fibrillin-1 cDNA demonstrated that fibrillin-1 is composed of a unique carboxyl terminus and two repetitive structural domains: the calcium-binding EGF-like (cbEGF) domain and a novel domain composed of eight cysteines (8 cys/TB). Completion of the remaining 5′ translated sequence suggested the presence of additional domains: two ‘hybrid’ domains, a proline-rich domain, four generic EGF domains, and a unique amino terminus. Sequence
Assembly of microfibrils
Like other structural macromolecules, fibrillins are designed to assemble into fibrous elements — ‘microfibrils’. Evidence suggesting that fibrillins are the major structural components of microfibrils include the following data: (1) fibrillin can be immunolocalized to microfibrils residing in all tissue locations; (2) immunolocalization of specific fibrillin epitopes results in periodic labeling of microfibrils, suggesting an ordered arrangement of fibrillin molecules within microfibrils (
Conclusions
Structural studies of fibrillins have informed our current thinking about how fibrillins assemble into microfibrils and how these molecules confer functional integrity to connective tissues. In this review, we have emphasized certain unresolved questions and controversial areas: which regions of fibrillin are rigid or flexible? Are fibrillins fully calcium-bound in vivo? Which domains in fibrillins participate in assembly of microfibrils? What role does cellular processing of fibrillins play in
Acknowledgements
PAH and AKD thank the support of the Royal Society, Wellcome Trust, and the MRC. This is a contribution from the Oxford Centre for Molecular Sciences which is supported by the BBSRC, MRC and EPSRC. DPR acknowledges support from the Deutsche Forschungsgemeinschaft. LYS thanks Hans Peter Bächinger and Douglas R. Keene for multiple very helpful discussions, and the Shriners Hospitals for Children for financial support.
References (51)
- et al.
Revised genomic organization of FBN1 and significance for regulated gene expression
Genomics
(1999) - et al.
Metal ion dependency of microfibrils supports a rod-like conformation for fibrillin-1 calcium-binding epidermal growth factor-like domains
J. Mol. Biol.
(1998) - et al.
Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders
Cell
(1996) - et al.
Characterization of the human gene for microfibril-associated glycoprotein (MFAP2), assignment to chromosome 1p36.1p35, and linkage to D1S170
Genomics
(1995) - et al.
Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4
Matrix Biol.
(1999) - et al.
Calcium binding hydroxylation, and glycosylation of the precursor epidermal growth factor-like domains of fibrillin-1, the Marfan gene protein
J. Biol. Chem.
(1994) - et al.
Identification and characterization of an eight-cysteine repeat of the latent transforming growth factor-beta binding protein-1 that mediates bonding to the latent transforming growth factor-betal
J. Biol. Chem.
(1996) - et al.
The calcium binding properties and molecular organization of epidermal growth factor-like domains in human fibrillin-1
J. Biol. Chem.
(1995) - et al.
Atomic force microscopy and modeling of natural elastic fibrillin polymers
Biol. Cell
(1998) - et al.
Defective calcium binding to fibrillin-1: consequence of an N2144S change for fibrillin-1 structure and function
J. Mol. Biol.
(1999)