scholarly journals Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists†

Biochemistry ◽  
2008 ◽  
Vol 47 (52) ◽  
pp. 13831-13841 ◽  
Author(s):  
Avinash Gill ◽  
Amanda Birdsey-Benson ◽  
Brian L. Jones ◽  
Leslie P. Henderson ◽  
Dean R. Madden
2014 ◽  
Vol 144 (6) ◽  
pp. 503-512 ◽  
Author(s):  
David M. MacLean ◽  
Swarna S. Ramaswamy ◽  
Mei Du ◽  
James R. Howe ◽  
Vasanthi Jayaraman

Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) markedly enhance AMPAR function, altering ligand efficacy and receptor gating kinetics and thereby shaping the postsynaptic response. The structural mechanism underlying TARP effects on gating, however, is unknown. Here we find that the prototypical member of the TARP family, stargazin or γ-2, rescues gating deficits in AMPARs carrying mutations that destabilize the closed-cleft states of the ligand-binding domain (LBD), suggesting that stargazin reverses the effects of these mutations and likely stabilizes closed LBD states. Furthermore, stargazin promotes a more closed conformation of the LBD, as indicated by reduced accessibility to the large antagonist NBQX. Consistent with the functional studies, luminescence resonance energy transfer experiments directly demonstrate that the AMPAR LBD is on average more closed in the presence of stargazin, in both the apo and agonist-bound states. The additional cleft closure and/or stabilization of the more closed-cleft states of the LBD is expected to translate to higher agonist efficacy and could contribute to the structural mechanism for stargazin modulation of AMPAR function.


2016 ◽  
Vol 110 (4) ◽  
pp. 896-911 ◽  
Author(s):  
Jelena Baranovic ◽  
Miriam Chebli ◽  
Hector Salazar ◽  
Anna L. Carbone ◽  
Katja Faelber ◽  
...  

2018 ◽  
Vol 10 (3) ◽  
pp. 243-247
Author(s):  
Saara Laulumaa ◽  
Kathrine Voigt Hansen ◽  
Magdalena Masternak ◽  
Thomas Drapier ◽  
Pierre Francotte ◽  
...  

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2491-2498 ◽  
Author(s):  
Jamie Rossjohn ◽  
William J. McKinstry ◽  
Joanna M. Woodcock ◽  
Barbara J. McClure ◽  
Timothy R. Hercus ◽  
...  

Abstract Heterodimeric cytokine receptors generally consist of a major cytokine-binding subunit and a signaling subunit. The latter can transduce signals by more than 1 cytokine, as exemplified by the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and IL-6 receptor systems. However, often the signaling subunits in isolation are unable to bind cytokines, a fact that has made it more difficult to obtain structural definition of their ligand-binding sites. This report details the crystal structure of the ligand-binding domain of the GM-CSF/IL-3/IL-5 receptor β-chain (βc) signaling subunit in complex with the Fab fragment of the antagonistic monoclonal antibody, BION-1. This is the first single antagonist of all 3 known eosinophil-producing cytokines, and it is therefore capable of regulating eosinophil-related diseases such as asthma. The structure reveals a fibronectin type III domain, and the antagonist-binding site involves major contributions from the loop between the B and C strands and overlaps the cytokine-binding site. Furthermore, tyrosine421 (Tyr421), a key residue involved in receptor activation, lies in the neighboring loop between the F and G strands, although it is not immediately adjacent to the cytokine-binding residues in the B-C loop. Interestingly, functional experiments using receptors mutated across these loops demonstrate that they are cooperatively involved in full receptor activation. The experiments, however, reveal subtle differences between the B-C loop and Tyr421, which is suggestive of distinct functional roles. The elucidation of the structure of the ligand-binding domain of βc also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems.


2018 ◽  
Vol 114 (3) ◽  
pp. 125a
Author(s):  
Hiraku Oshima ◽  
Suyong Re ◽  
Masayoshi Sakakura ◽  
Hideo Takahashi ◽  
Yuji Sugita

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