Molecular evolution of the fibulins: Implications on the functionality of the elastic fibulins

The fibulins form a family of secreted proteins associated with the basement membrane, cell adhesive structures, and elastic fibers characterized by the presence of a unique fibulin-like C-terminal domain preceded by a rod-like tandem array of calcium-binding EGF modules. We traced the origin of the fibulin gene family to the base of the metazoans. In invertebrates, Fibulin-1 and Hemicentin comprise the fibulin gene set. Diversification of the fibulins took place in the last common ancestor to the chordates by gene duplication of an ancestral Fibulin-1 gene. Further duplications at the vertebrate stem and in teleost fishes increased the number of fibulin genes to nine, including the novel Fibulin-8. Extensive gene loss has happened repeatedly, including Fibulin-8 in placental mammals and Fibulin-4 in birds. The Fibulin-3/4/5 clade of elastic fibulins branched out at the sequence level after relaxation of selective constraints immediately after the two gene duplication events in quick succession that originated the individual vertebrate Fibulin-3, -4, and -5 genes. Divergence took place mostly in the Fibulin-5 branch, at the atypical first EGF module and at the fibulin-like C-terminal region. Differentiation in gene expression further split Fibulin-5 from the other elastic fibulins, likely contributing to its nonredundant role in elastic fiber assembly.