Abstract
In many families of cell surface receptors, a single transmembrane (TM) α-helix separates ecto- and cytosolic domains. A defined coupling of ecto- and TM domains must be essential to allosteric receptor regulation but remains little understood. Here, we characterize the linker structure, dynamics, and resulting ecto-TM domain coupling of integrin αIIb in model constructs and relate it to other integrin α subunits by mutagenesis. Cellular integrin activation assays subsequently validate the findings in intact receptors. Our results indicate a flexible yet carefully tuned ecto-TM coupling that modulates the signaling threshold of integrin receptors. Interestingly, a proline at the N-terminal TM helix border, termed NBP, is critical to linker flexibility in integrins. NBP is further predicted in 21% of human single-pass TM proteins and validated in cytokine receptors by the TM domain structure of the cytokine receptor common subunit β and its P441A-substituted variant. Thus, NBP is a conserved uncoupling motif of the ecto-TM domain transition and the degree of ecto-TM domain coupling represents an important parameter in the allosteric regulation of diverse cell surface receptors.
Highlights
Cells sense their environment through transmembrane (TM)3 surface receptors that transmit extracellular signals into the cell
Thermodynamic Description of Ectodomain-TM Domain Coupling—To obtain a simple model of integrin activation, we decompose the free energy required to activate the receptor into two terms
On structural and functional levels, such variations adjust the degree of ecto-TM domain coupling (Fig. 3C) and control receptor activation thresholds (Fig. 4C)
Summary
Cells sense their environment through transmembrane (TM)3 surface receptors that transmit extracellular signals into the cell. We characterize the linker structure, dynamics, and resulting ecto-TM domain coupling of integrin ␣IIb in model constructs and relate it to other integrin ␣ subunits by mutagenesis. This coupling and associated allosteric parameters must depend on the structural and dynamic properties of the linker between ecto- and TM domains.
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