2na9

Publication Abstract from PubMed

In many families of cell surface receptors, a single transmembrane (TM) alpha-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 alphaIIb in model constructs and relate it to other integrin alpha 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 sets 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 beta 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.

A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors.,Schmidt T, Ye F, Situ AJ, An W, Ginsberg MH, Ulmer TS J Biol Chem. 2016 Jun 30. pii: jbc.M116.733683. PMID:27365391^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.