The Evolution of Extracellular Fibrillins and Their Functional Domains

Abstract

Fibrillins constitute the major backbone of multifunctional microfibrils in elastic and non-elastic extracellular matrices, and are known to interact with several binding partners including tropoelastin and integrins. Here, we study the evolution of fibrillin proteins. Following sequence collection from 39 organisms representative of the major evolutionary groups, molecular evolutionary genetics and phylogeny inference software were used to generate a series of evolutionary trees using distance-based and maximum likelihood methods. The resulting trees support the concept of gene duplication as a means of generating the three vertebrate fibrillins. Beginning with a single fibrillin sequence found in invertebrates and jawless fish, a gene duplication event, which coincides with the appearance of elastin, led to the creation of two genes. One of the genes significantly evolved to become the gene for present-day fibrillin-1, while the other underwent evolutionary changes, including a second duplication, to produce present-day fibrillin-2 and fibrillin-3. Detailed analysis of several sequences and domains within the fibrillins reveals distinct similarities and differences across various species. The RGD integrin-binding site in TB4 of all fibrillins is conserved in cephalochordates and vertebrates, while the integrin-binding site within cbEGF18 of fibrillin-3 is a recent evolutionary change. The proline-rich domain in fibrillin-1, glycine-rich domain in fibrillin-2 and proline-/glycine-rich domain in fibrillin-3 are found in all analyzed tetrapod species, whereas it is completely replaced with an EGF-like domain in cnidarians, arthropods, molluscs and urochordates. All collected sequences contain the first 9-cysteine hybrid domain, and the second 8-cysteine hybrid domain with exception of arthropods containing an atypical 10-cysteine hybrid domain 2. Furin cleavage sites within the N- and C-terminal unique domains were found for all analyzed fibrillin sequences, indicating an essential role for processing of the fibrillin pro-proteins. The four cysteines in the unique N-terminus and the two cysteines in the unique C-terminus are also highly conserved.

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…7,9,10,18 From an evolutionary perspective, the domain organization of fibrillin-1 is remarkably conserved, with the number and kinds of domains nearly identical from jellyfish to human, consistent with a central biological role for microfibrils. 18,19 The bulk of fibrillin-1 structure is composed of 47 epidermal growth factor (EGF)-like domains, 43 of which bind calcium (cb-EGF-like). 7 EGF-like and cb-EGF-like domains are relatively common, occurring in many proteins other than fibrillins, and often serving as binding sites for other proteins.…”

“…18 In humans, there are 3 fibrillins that are distinguishable by a domain located C-terminal from the first TB domain, which is proline-rich for fibrillin-1, glycine-rich for fibrillin-2 and proline, and glycine-rich for fibrillin-3. 18,19 The domain structure is almost completely preserved in the 3 fibrillins, with the notable exception that fibrillin-2 and fibrillin-3 contain an additional RGD motif in addition to the one found within the fourth TB domain of fibrillin-1. 18,19 Fibrillin-1 is by far the best-studied and most prevalent fibrillin, forming the backbone of mature microfibrils.…”

“…18,19 The domain structure is almost completely preserved in the 3 fibrillins, with the notable exception that fibrillin-2 and fibrillin-3 contain an additional RGD motif in addition to the one found within the fourth TB domain of fibrillin-1. 18,19 Fibrillin-1 is by far the best-studied and most prevalent fibrillin, forming the backbone of mature microfibrils. Fibrillin-2 is also found in microfibrils and probably shares many of the functional capabilities of fibrillin-1 since it may be able to partially compensate for fibrillin-1 deficiency.…”

Marfanoid–progeroid–lipodystrophy syndrome: a newly recognized fibrillinopathy

“…17 Defective microfibril function will affect the formation and organization of fibrillin monomers within microfibrils, and interfere with the structure and function of the extracellular matrix in general. As the C-terminal globular domain of fibrillin-1 is structurally similar to other extracellular matrix proteins, fibulin-3 and fibulin4, 18,19 the functional loss of this segment might be critical for the pathogenesis of the progeroid form of MFS. As not all mutations in exon 64 nor all premature truncation or splice site mutations in the 3′ exons of FBN1 are associated with the progeroid phenotype, 7 the frameshift mutations described in the progeroid form of MFS must alter the function of fibrillin-1 in some specific way.…”

C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43

“…Just before or after secretion, the propeptide sequences from the N and C termini are cleaved by furin (Fig. 1A) (3)(4)(5)(6) at sites that have been conserved through evolution (7,8). A regulatory role for the C-terminal propeptide was suggested by a study of a MFS-associated R2726W substitution in fibrillin-1 (9), which resulted in a loss of mutant Cterminal processing and a lack of incorporation of the unprocessed material into the insoluble matrix of cultured dermal fibroblasts.…”