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Zhu, Jianghai

Publications and source records attributed to Zhu, Jianghai.

8 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Force interacts with macromolecular structure in activation of TGF-β

Integrins are adhesion receptors that transmit force across the plasma membrane between extracellular ligands and the actin cytoskeleton. In activation of the transforming growth factor-β1 precursor (pro-TGF-β1), integrins bind to the prodomain, apply force, and release the TGF-β growth factor. However, we know little about how integrins bind macromolecular ligands in the extracellular matrix or transmit force to them. Here we show how integrin α V β 6 binds pro-TGF-β1 in an orientation biologically relevant for force-dependent release of TGF-β from latency. The conformation of the prodomain integrin-binding motif differs in the presence and absence of integrin binding; differences extend well outside the interface and illustrate how integrins can remodel extracellular matrix. Remodelled residues outside the interface stabilize the integrin-bound conformation, adopt a conformation similar to earlier-evolving family members, and show how macromolecular components outside the binding motif contribute to integrin recognition. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF-β orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin β-subunit. Simulations of force-dependent activation of TGF-β demonstrate evolutionary specializations for force application through the TGF-β prodomain and through the β- and not α-subunit of the integrin.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

β-Subunit Binding Is Sufficient for Ligands to Open the Integrin α IIb β 3 Headpiece

The platelet integrin α IIb β 3 binds to a KQAGDV motif at the fibrinogen γ-chain C terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin α and β-subunits; the basic Lys or Arg side chain hydrogen bonds to the α IIb -subunit, and the acidic Asp side chain coordinates to a metal ion held by the β 3 -subunit. Ligand binding induces headpiece opening, with conformational change in the β-subunit. During this opening, RGD slides in the ligand-binding pocket toward α IIb , with movement of the βI-domain β1-α1 loop toward α IIb , enabling formation of direct, charged hydrogen bonds between the Arg side chain and α IIb . Here we test whether ligand interactions with β 3 suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the α IIb β 3 headpiece with affinity comparable with the RGDSP peptide from fibronectin. AGDV induced complete headpiece opening in solution as shown by increase in hydrodynamic radius. Soaking of AGDV into closed α IIb β 3 headpiece crystals induced intermediate states similarly to RGDSP. AGDV has very little contact with the α-subunit. Furthermore, as measured by epitope exposure, AGDV, like the fibrinogen γ C-terminal peptide and RGD, caused integrin extension on the cell surface. Thus, pushing by the β 3 -subunit on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the α IIb subunit on Arg is required.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗