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Structural determinants of integrin β-subunit specificity for latent TGF-β
Xianchi Dong1, Nathan E Hudson1, Chafen Lu1
11] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Structural & Molecular Biology
|November 11, 2014
Summary
Integrins bind proteins using an Arg-Gly-Asp (RGD) motif. This study reveals how integrin αVβ6 specifically recognizes the RGDLXXL/I motif in TGF-β1/β3, uncovering key structural details for ligand specificity.
Area of Science:
- Molecular biology
- Structural biology
- Biochemistry
Background:
- Integrins are cell surface receptors that mediate cell adhesion.
- Eight integrin α-β heterodimers recognize ligands containing the Arg-Gly-Asp (RGD) motif.
- The structural basis for integrin specificity among RGD-containing ligands remains unclear.
Purpose of the Study:
- To elucidate the structural mechanism by which integrin αVβ6 differentiates and binds to specific RGD-containing ligands.
- To identify the structural determinants of ligand binding specificity in the integrin β6 subunit.
Main Methods:
- X-ray crystallography to determine protein structures.
- Site-directed mutagenesis to investigate protein function.
- Peptide-affinity measurements to quantify binding interactions.
Main Results:
- Integrin αVβ6 exhibits high affinity for the RGDLXXL/I motif found in the prodomains of TGF-β1 and TGF-β3.
- The LXXL/I motif forms an α-helix that docks into a hydrophobic pocket within the β6 subunit.
- Three specificity-determining loops (SDLs) in the βI-domain of the β6 subunit contribute to ligand binding specificity.
- Key residue variations in SDL1 and SDL3 correlate with β-subunit evolution, suggesting a broader role in integrin function.
Conclusions:
- The study reveals the structural basis for αVβ6 integrin specificity towards TGF-β1/β3 via the RGDLXXL/I motif.
- Specificity-determining loops (SDLs) in the β6 integrin subunit are critical for ligand recognition.
- Evolutionary analysis of SDLs suggests their fundamental role in β-subunit function and integrin diversity.
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