Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites

Robert N. Ono, Gerhard Sengle, Noel L. Charbonneau, Valerie Calberg, Hans Peter Bächinger, Takako Sasaki, Sui Lee-Arteaga, Lior Zilberberg, Daniel B. Rifkin, Francesco Ramirez, Mon Li Chu, Lynn Sakai

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Latent transforming growth factor (TGF) β-binding proteins (LTBPs) interact with fibrillin-1. This interaction is important for proper sequestration and extracellular control of TGFβ. Surface plasmon resonance interaction studies show that residues within the first hybrid domain (Hyb1) of fibrillin-1 contribute to interactions with LTBP-1 and LTBP-4. Modulation of binding affinities by fibrillin-1 polypeptides in which residues in the third epidermal growth factor-like domain (EGF3) are mutated demonstrates that the binding sites for LTBP-1 and LTBP-4 are different and suggests that EGF3 may also contribute residues to the binding site for LTBP-4. In addition, fibulin-2, fibulin-4, and fibulin-5 bind to residues contained within EGF3/Hyb1, but mutated polypeptides again indicate differences in their binding sites in fibrillin-1. Results demonstrate that these protein-protein interactions exhibit "exquisite specificities," a phrase commonly used to describe monoclonal antibody interactions. Despite these differences, interactions between LTBP-1 and fibrillin-1 compete for interactions between fibrillin-1 and these fibulins. All of these proteins have been immunolocalized to microfibrils. However, in fibrillin-1 (Fbn1) null fibroblast cultures, LTBP-1 and LTBP-4 are not incorporated into microfibrils. In contrast, in fibulin-2 (Fbln2) null or fibulin-4 (Fbln4) null cultures, fibrillin-1, LTBP-1, and LTBP-4 are incorporated into microfibrils. These data show for the first time that fibrillin-1, but not fibulin-2 or fibulin-4, is required for appropriate matrix assembly of LTBPs. These studies also suggest that the fibulins may affect matrix sequestration of LTBPs, because in vitro interactions between these proteins are competitive.

Original languageEnglish (US)
Pages (from-to)16872-16881
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number25
DOIs
StatePublished - Jun 19 2009

Fingerprint

Transforming Growth Factors
Carrier Proteins
Binding Sites
Microfibrils
Proteins
Peptides
Surface plasmon resonance
Fibroblasts
Cell culture
Epidermal Growth Factor
Monoclonal Antibodies
Modulation
fibulin
Fibrillin-1
Surface Plasmon Resonance
fibulin-4
fibulin 2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. / Ono, Robert N.; Sengle, Gerhard; Charbonneau, Noel L.; Calberg, Valerie; Bächinger, Hans Peter; Sasaki, Takako; Lee-Arteaga, Sui; Zilberberg, Lior; Rifkin, Daniel B.; Ramirez, Francesco; Chu, Mon Li; Sakai, Lynn.

In: Journal of Biological Chemistry, Vol. 284, No. 25, 19.06.2009, p. 16872-16881.

Research output: Contribution to journalArticle

Ono, RN, Sengle, G, Charbonneau, NL, Calberg, V, Bächinger, HP, Sasaki, T, Lee-Arteaga, S, Zilberberg, L, Rifkin, DB, Ramirez, F, Chu, ML & Sakai, L 2009, 'Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites', Journal of Biological Chemistry, vol. 284, no. 25, pp. 16872-16881. https://doi.org/10.1074/jbc.M809348200
Ono, Robert N. ; Sengle, Gerhard ; Charbonneau, Noel L. ; Calberg, Valerie ; Bächinger, Hans Peter ; Sasaki, Takako ; Lee-Arteaga, Sui ; Zilberberg, Lior ; Rifkin, Daniel B. ; Ramirez, Francesco ; Chu, Mon Li ; Sakai, Lynn. / Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 25. pp. 16872-16881.
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AU - Bächinger, Hans Peter

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