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PMID: 10930463 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta.

Molecular biology of the cell ·Vol. 11 ·No. 8 ·2000-08-00 ·Pages 2691-704

Saharinen J, Keski-Oja J

Abstract

Transforming growth factor (TGF)-betas are secreted in large latent complexes consisting of TGF-beta, its N-terminal latency-associated peptide (LAP) propeptide, and latent TGF-beta binding protein (LTBP). LTBPs are required for secretion and subsequent deposition of TGF-beta into the extracellular matrix. TGF-beta1 associates with the 3(rd) 8-Cys repeat of LTBP-1 by LAP. All LTBPs, as well as fibrillins, contain multiple 8-Cys repeats. We analyzed the abilities of fibrillins and LTBPs to bind latent TGF-beta by their 8-Cys repeats. 8-Cys repeat was found to interact with TGF-beta1*LAP by direct cysteine bridging. LTBP-1 and LTBP-3 bound efficiently all TGF-beta isoforms, LTBP-4 had a much weaker binding capacity, whereas LTBP-2 as well as fibrillins -1 and -2 were negative. A short, specific TGF-beta binding motif was identified in the TGF-beta binding 8-Cys repeats. Deletion of this motif in the 3(rd) 8-Cys repeat of LTBP-1 resulted in loss of TGF-beta*LAP binding ability, while its inclusion in non-TGF-beta binding 3(rd) 8-Cys repeat of LTBP-2 resulted in TGF-beta binding. Molecular modeling of the 8-Cys repeats revealed a hydrophobic interaction surface and lack of three stabilizing hydrogen bonds introduced by the TGF-beta binding motif necessary for the formation of the TGF-beta*LAP - 8-Cys repeat complex inside the cells.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Carrier Proteins/chemistry,genetics,metabolism Cysteine/chemistry Epithelial Cells Fibrillins Fibroblasts Humans Intracellular Signaling Peptides and Proteins Latent TGF-beta Binding Proteins Microfilament Proteins/chemistry,metabolism Models, Molecular Molecular Sequence Data Protein Binding Protein Isoforms/chemistry,genetics,metabolism Protein Structure, Tertiary Recombinant Fusion Proteins/metabolism Sequence Alignment Transfection Transforming Growth Factor beta/chemistry,genetics,metabolism
Chemicals
Carrier Proteins Fibrillins Intracellular Signaling Peptides and Proteins LTBP1 protein, human LTBP2 protein, human LTBP3 protein, human LTBP4 protein, human Latent TGF-beta Binding Proteins Microfilament Proteins Protein Isoforms Recombinant Fusion Proteins Transforming Growth Factor beta Cysteine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Saharinen J
Departments of Virology and Pathology, The Haartman Institute, University of Helsinki, Finland.
Keski-Oja J
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.11.8.2691
Published
2000-08-00
Pages
2691-704
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC14949
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.11.8.2691 PMC Full Text View journal details
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