Identification of a Major Microfibril-associated Glycoprotein-1-binding Domain in Fibrillin-2

Abstract

Microfibrils are found in the extracellular matrices of most tissues where they serve several functional roles, including the binding and sequestration of growth factors, supplying informational signals through receptor signaling, and providing the basic structural elements for elastic fiber assembly. Many different proteins have been localized to microfibrils, although it is not clear whether all are structural proteins or proteins that simply associate with other components of microfibrils (1, 2).The fibrillins provide the basic functional framework of microfibrils. This multigene family consists of three related proteins (fibrillin-1, -2, and -3) that have a similar domain structure but differ in expression pattern and biological function (3). The fibrillins are secreted from the cell as dimers that then pack together in ways that are not completely understood to form the microfibril. Extracted microfibrils are typically visualized as a linear string of beads with multiple arms extending into the interbead region. The beads show a ϳ50-nm spacing, and several models of fibrillin assembly have been proposed to account for packing a 150-nm fibrillin monomer into a structure with 50-nm periodicity (4, 5).A second protein associated with microfibrils is a small molecular mass glycoprotein called microfibril-associated glycoprotein. MAGP-1 1 contains 183 amino acids that form two distinctive domains; the N-terminal half of the molecule is highly acidic, enriched in proline, and contains a clustering of glutamine residues, whereas the C-terminal portion contains all 13 cysteine residues and contains the matrix-binding domain that mediates the association of MAGP-1 with microfibrillar components (6). The protein undergoes post-translational transglutamination, sulfation of specific tyrosine residues, and O-linked glycosylation (7). In mouse development, MAGP-1 mRNA is widely expressed, mainly in mesenchymal and connective tissue cells where it is easily detected as early as day 8.5 of development (8). MAGP-1 is associated with all microfibrils with only two known exceptions: those directly adjacent to the plasma membrane of aortic endothelial cells and those at the junction of the zonule and the lens capsule of the eye (9 -11).MAGP-2 is a second member of the MAGP family that has close sequence similarity to MAGP-1 in a central region of 60 amino acids, where the spacing of 7 cysteine residues is identical in both proteins. The MAGP-2 molecule is otherwise rich in serine and threonine residues and lacks the proline-, glutamine-, and tyrosine-rich sequences characteristic of the Nterminal domain of MAGP-1 (12-15). MAGP-2 exhibits a more restricted pattern of tissue localization and developmental expression than MAGP-1 (15), suggesting that MAGP-1 and MAGP-2 are structurally divergent proteins sharing one functional motif (encoded by two conserved exons) rather than being functionally closely related molecules. Both MAGPs have been shown to directly bind to purified fibrillin, and for MAGP-2, a prominent binding site w...

New insights into elastic fiber assembly

“…MAGP-1 has also been shown to bind to fibrillin-2 in yeast two-hybrid, ligand blotting, and solid phase binding assays (Werneck et al, 2004). MAGP-2 binds to fibrillin-1 and -2 in yeast twohybrid studies (Penner et al, 2002) and in solid phase binding assays (Hanssen et al, 2004).…”

Molecular pathogenesis and management strategies of ectopia lentis

“…10 The bead-like structures are mostly encoded for by exon 24 of FBN1. 11 Mutations in this exon lead to severe Marfan syndrome (MFS). Other constituents of ZF include elastin, proteoglycans, and GAGs.…”

Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

“…The C-terminal half contains all of the molecule's thirteen cysteine residues and encodes a 54-amino acid sequence that defines a matrix-binding domain that targets MAGP-1 to the ECM. MAGP-1 binds to tropoelastin and type VI collagen (11,12) and interacts with other molecules with defined structural roles in the ECM such as fibrillin-1 and -2 (13,14), decorin (15), and biglycan (16). It does not, however, bind to the interstitial collagens I, III, or V (12).…”