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

Del Cid, Joselyn S., Isik Reed, Nilgun, Molnar, Kathleen, Liu, Sean, Dang, Bobo, Jensen, Sacha A., DeGrado, William, Handford, Penny, Sheppard, Dean, and Sundaram, Aparna B. (2019) A disease associated mutation in fibrillin-1 differentially regulates integrin mediated cell adhesion. Journal of Biological Chemistry, 294 (48). pp. 18232-18243.

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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 β (TGFβ)-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 α5β1, αvβ5, and αvβ6, partially inhibited adhesion mediated by αvβ1, and did not inhibit adhesion mediated by α8β1 or αIIbβ3. Adhesion mediated by integrin αvβ3 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.

Item ID: 60805
Item Type: Article (Research - C1)
ISSN: 1083-351X
Copyright Information: © 2019 Del Cid et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc
Date Deposited: 18 Dec 2019 06:19
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310109 Proteomics and intermolecular interactions (excl. medical proteomics) @ 50%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310105 Cellular interactions (incl. adhesion, matrix, cell wall) @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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