scholarly journals Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Sun-Joo Lee ◽  
Shizhen Wang ◽  
William Borschel ◽  
Sarah Heyman ◽  
Jacob Gyore ◽  
...  
Keyword(s):  
Binding Site ◽  
Inward Rectifier ◽  
Anionic Phospholipid ◽  
Phospholipid Binding ◽  
Gating Mechanism ◽  
Inward Rectifier Channels

scholarly journals Unique Anionic Phospholipid Binding Site and Gating Mechanism in Kir2.1 Inward Rectifier Channels

2014 ◽  
Vol 106 (2) ◽  
pp. 747a-748a
Author(s):  
Sun Joo Lee ◽  
Shizhen Wang ◽  
William Borschel ◽  
Sarah Heyman ◽  
Jacob Gyore ◽  
...  
Keyword(s):  
Binding Site ◽  
Inward Rectifier ◽  
Anionic Phospholipid ◽  
Phospholipid Binding ◽  
Gating Mechanism ◽  
Inward Rectifier Channels

scholarly journals Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells

2009 ◽  
Vol 47 (1) ◽  
pp. 121-132 ◽  
Author(s):  
Z. Maggie Huang ◽  
Chaithra Prasad ◽  
Fiona C. Britton ◽  
Linda L. Ye ◽  
William J. Hatton ◽  
...  
Keyword(s):  
Functional Role ◽  
Inward Rectifier ◽  
Pacemaker Cells ◽  
Inward Rectifier Channels

scholarly journals Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids

2016 ◽  
Vol 148 (3) ◽  
pp. 227-237 ◽  
Author(s):  
Sun-Joo Lee ◽  
Feifei Ren ◽  
Eva-Maria Zangerl-Plessl ◽  
Sarah Heyman ◽  
Anna Stary-Weinzinger ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Membrane Lipids ◽  
Inward Rectifier ◽  
Primary Site ◽  
Structural Basis ◽  
Channel Activity ◽  
Anionic Phospholipid ◽  
X Ray ◽  
Anionic Phospholipids ◽  
Kir Channel

Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol-4,5-bisphosphate (PIP2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL−) with a distinct second site is required for high PIP2 sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP2 sensitivity, even in the absence of PL−. Furthermore, high-resolution x-ray crystal structures of Kir2.2[K62W], with or without added PIP2 (2.8- and 2.0-Å resolution, respectively), reveal tight tethering of the C-terminal domain (CTD) to the transmembrane domain (TMD) in each condition. Our results suggest a refined model for phospholipid gating in which PL− binding at the second site pulls the CTD toward the membrane, inducing the formation of the high-affinity primary PIP2 site and explaining the positive allostery between PL− binding and PIP2 sensitivity.

scholarly journals The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site.

1996 ◽  
Vol 93 (16) ◽  
pp. 8312-8317 ◽  
Author(s):  
H. R. Mott ◽  
J. W. Carpenter ◽  
S. Zhong ◽  
S. Ghosh ◽  
R. M. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Solution Structure ◽  
Phospholipid Binding ◽  
Rich Domain ◽  
Cysteine Rich Domain

Autoreactive CD4+ T-cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1889-1896 ◽  
Author(s):  
Takahide Arai ◽  
Kazue Yoshida ◽  
Junichi Kaburaki ◽  
Hidetoshi Inoko ◽  
Yasuo Ikeda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Binding Site ◽  
Antibody Production ◽  
Cd40 Ligand ◽  
Antiphospholipid Antibody ◽  
T Cell Clones ◽  
Major Phospholipid ◽  
Phospholipid Binding ◽  
Cell Clones

Abstract Autoreactive CD4+ T cells to β2-glycoprotein I (β2GPI) that promote antiphospholipid antibody production were recently identified in patients with antiphospholipid syndrome (APS). To further examine antigen recognition profiles and T-cell helper activity in β2GPI-reactive T cells, 14 CD4+ T-cell clones specific to β2GPI were generated from 3 patients with APS by repeated stimulation of peripheral blood T cells with recombinant β2GPI. At least 4 distinct T-cell epitopes were identified, but the majority of the β2GPI-specific T-cell clones responded to a peptide encompassing amino acid residues 276 to 290 of β2GPI (KVSFFCKNKEKKCSY; single-letter amino acid codes) that contains the major phospholipid-binding site in the context of the DRB4*0103 allele. Ten of 12 β2GPI-specific T-cell clones were able to stimulate autologous peripheral blood B cells to promote anti-β2GPI antibody production in the presence of recombinant β2GPI. T-cell helper activity was exclusively found in T-cell clones capable of producing interleukin 6 (IL-6). In vitro anti-β2GPI antibody production induced by T-cell clones was inhibited by anti-IL-6 or anti-CD40 ligand monoclonal antibody. In addition, exogenous IL-6 augmented anti-β2GPI antibody production in cultures of the T-cell clone lacking IL-6 expression. These results indicate that β2GPI-specific CD4+ T cells in patients with APS preferentially recognize the antigenic peptide containing the major phospholipid-binding site and have the capacity to stimulate B cells to produce anti-β2GPI antibodies through IL-6 expression and CD40-CD40 ligand engagement. These findings are potentially useful for clarifying the pathogenesis of APS and for developing therapeutic strategies that suppress pathogenic antiphospholipid antibody production in these patients.

scholarly journals Pathophysiology of the Antiphospholipid Antibody Syndrome

2021 ◽  
Author(s):  
David Green
Keyword(s):  
Antiphospholipid Syndrome ◽  
Binding Proteins ◽  
Membrane Receptors ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Clotting Factors ◽  
Anionic Phospholipid ◽  
Autoantibody Production ◽  
Phospholipid Binding ◽  
Glycoprotein I

The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β2-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the “lupus anticoagulant”. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β2-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production.

Functional comparison of plant inward-rectifier channels expressed in yeast

1997 ◽  
Vol 48 (Special) ◽  
pp. 405-413 ◽  
Author(s):  
A. Bertl ◽  
J. D. Reid ◽  
H. Sentenac ◽  
C. L. Slayman
Keyword(s):  
Inward Rectifier ◽  
Inward Rectifier Channels
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