The Eighth FIII Domain of Human Fibronectin Promotes Integrin α5β1 Binding via Stabilization of the Ninth FIII Domain

Altroff, Harri; Walle, Christopher F. van der; Asselin, J; Fairless, Richard; Campbell, Iain D.; Mardon, Helen J.

doi:10.1074/jbc.m105868200

Cited by 69 publications

(80 citation statements)

References 30 publications

(36 reference statements)

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“…1A, the blocked PHSRN peptide stimulated invasion by HME with a log-linear dose-response relationship at concentrations from 10 ng/mL to 1 g/mL (17 nmol/L to 1.7 mol/L), whereas the scrambled, blocked PHSRN peptide, Ac-HSPNR-NH 2 , was without detectable activity at 17 mol/L. In addition to PHSRN (32), ␣ 5 ␤ 1 interacts with the RGD (8) and VKNEED sequences of the fibronectin cell binding domain (33). Thus, the acetylated, amidated derivatives of these peptides were also tested for invasion induction.…”

Section: Resultsmentioning

confidence: 99%

Integrin Fibronectin Receptors in Matrix Metalloproteinase-1–Dependent Invasion by Breast Cancer and Mammary Epithelial Cells

et al. 2004

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Integrins contribute to progression in many cancers, including breast cancer. For example, the interaction of ␣ 5 ␤ 1 with plasma fibronectin causes the constitutive invasiveness of human prostate cancer cells. Inhibition of this process reduces tumorigenesis and prevents metastasis and recurrence. In this study, naturally serum-free basement membranes were used as invasion substrates. Immunoassays were used to compare the roles of

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Section: Resultsmentioning

confidence: 99%

Integrin Fibronectin Receptors in Matrix Metalloproteinase-1–Dependent Invasion by Breast Cancer and Mammary Epithelial Cells

et al. 2004

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“…This is likely due to loss of the Pro-HisSer-Arg-Asn (PHSRN) sequence in FNIII9, which acts synergistically with the RGD sequence to bind a5b1 integrins. 5 Although mutating the PHSRN sequence in recombinant FNIII9-10 reduces a5b1 integrin-binding compared to intact FNIII9-10, 52 addition of FNIII8 to the mutated construct rescued the loss in a5b1 integrin binding, suggesting that FNIII8 can function much like FNIII9 to stabilize the interaction between FNIII10 and a5b1 integrins. 52 These data are consistent with the results of our integrin-blocking studies with GST/III1H,8,10, where the presence of both FNIII8 and FNIII10 supported a5b1 integrin adhesion independent of the PHSRN site in FNIII9.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Fibronectin Matrix Mimetics Specify Integrin Adhesion and Extracellular Matrix Assembly

Roy

Hocking

2013

Tissue Engineering Part A

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Tissue engineering seeks to create functional tissues and organs by integrating natural or synthetic scaffolds with bioactive factors and cells. Creating biologically active scaffolds that support key aspects of tissue regeneration, including the re-establishment of a functional extracellular matrix (ECM), is a challenge currently facing this field. During tissue repair, fibronectin is converted from an inactive soluble form into biologically active ECM fibrils through a cell-dependent process. ECM fibronectin promotes cell processes critical to tissue regeneration and regulates the deposition and organization of other ECM proteins. We previously developed biomimetics of ECM fibronectin by directly coupling the heparin-binding fragment of the first type III repeat of fibronectin (FNIII1H) to the integrin-binding repeats (FNIII8-10). As adhesive substrates, fibronectin matrix mimetics promote cell growth, migration, and contractility through a FNIII1H-dependent mechanism. Here, we analyzed fibronectin matrix mimetic variants designed to include all or part of the integrin-binding domain for their ability to support new ECM assembly. We found that specific modifications of the integrin-binding domain produced adhesive substrates that selectively engage different integrin receptors to, in turn, regulate the amount of fibronectin and collagen deposited into the ECM. The ability of fibronectin matrix mimetics to direct cellsubstrate interactions and regulate ECM assembly makes them promising candidates for use as bioactive surfaces, where precise control over integrin-binding specificity and ECM deposition are required.

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“…In addition to the RGD motif of FnIII10, FnIII also requires module 9 for optimal integrin-binding affinity (47). Two charged residues in module 9 (FnIII9) have been shown to be critical for binding to ␣ 5 ␤ 1 integrin.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

Auperin

Bolduc

Baron

et al. 2005

Journal of Biological Chemistry

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Group B Streptococcus (GBS) is the leading cause of bacterial pneumonia, sepsis, and meningitis among neonates and an important cause of morbidity among pregnant women and immunocompromised adults. Invasive diseases due to GBS are attributed to the ability of the pathogen to translocate across human epithelial surfaces. The alpha C protein (ACP) has been identified as an invasin that plays a role in internalization and translocation of GBS across epithelial cells. The soluble N-terminal domain of ACP (NtACP) blocks the internalization of GBS. We determined the 1.86-Å resolution crystal structure of NtACP comprising residues Ser 52 through Leu 225 of the full-length ACP. NtACP has two domains, an N-terminal ␤-sandwich and a C-terminal three-helix bundle. Structural and topological alignments reveal that the ␤-sandwich shares structural elements with the type III fibronectin fold (FnIII), but includes structural elaborations that make it unique. We have identified a potential integrin-binding motif consisting of Lys-Thr-Asp 146 , Arg 110 , and Asp 118 . A similar arrangement of charged residues has been described in other invasins. ACP shows a heparin binding activity that requires NtACP. We propose a possible heparin-binding site, including one surface of the three-helix bundle, and nearby portions of the sandwich and repeat domains. We have validated this prediction using assays of the heparin binding and cell-adhesion properties of engineered fragments of ACP. This is the first crystal structure of a member of the highly conserved Gram-positive surface alpha-like protein family, and it will enable the internalization mechanism of GBS to be dissected at the atomic level.Group B Streptococcus (GBS) 1 (Streptococcus agalactiae) remains the leading cause of invasive bacterial diseases in neonates, despite its decline in prevalence during the last decade because of intrapartum chemoprophylatic therapy (1, 2). It is also an important cause of morbidity in pregnant women and non-pregnant adults with underlying medical conditions (3-5). GBS colonizes the human gastrointestinal and genitourinary tracts and may cause chorioamnionitis and urinary tract infection in pregnant women and a range of invasive infections in elderly and immunocompromised adults (1, 6 -8). During labor and delivery, GBS may be transmitted to neonates, causing pneumonia, sepsis, or meningitis. Four to six percent of all neonatal GBS infections result in death (6, 9). In vitro, GBS adheres to (10, 11), internalizes within (12-14), and translocates across (15) intact human epithelial and endothelial cells. Little is known about the bacterial components that allow this pathogen to adhere to and penetrate cellular membranes. Previous studies suggest that surface proteins are significantly involved in the process (11, 16). The surface-expressed GBS alpha C protein (ACP) has been shown to act as an invasin (15). ACP is the prototype of a family of surface-expressed proteins containing long tandem repeats (alpha-like proteins (Alp)). Members of this famil...

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The Eighth FIII Domain of Human Fibronectin Promotes Integrin α5β1 Binding via Stabilization of the Ninth FIII Domain

Cited by 69 publications

References 30 publications

Integrin Fibronectin Receptors in Matrix Metalloproteinase-1–Dependent Invasion by Breast Cancer and Mammary Epithelial Cells

Integrin Fibronectin Receptors in Matrix Metalloproteinase-1–Dependent Invasion by Breast Cancer and Mammary Epithelial Cells

Recombinant Fibronectin Matrix Mimetics Specify Integrin Adhesion and Extracellular Matrix Assembly

Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

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