A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.

ABSTRACT: Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor ? (TGF?)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins ?5?1, ?v?5, and ?v?6, partially inhibited adhesion mediated by ?v?1, and did not inhibit adhesion mediated by ?8?1 or ?IIb?3. Adhesion mediated by integrin ?v?3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins.

SUBMITTER: Del Cid JS 

PROVIDER: S-EPMC6885615 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature