TY - JOUR
T1 - NhaA crystal structure
T2 - Functional-structural insights
AU - Padan, Etana
AU - Kozachkov, Lena
AU - Herz, Katia
AU - Rimon, Abraham
PY - 2009/6/1
Y1 - 2009/6/1
N2 - Na+/H+ antiporters are integral membrane proteins that exchange Na+ for H+ across the cytoplasmic membrane and many intracellular membranes. They are essential for Na+, pH and volume homeostasis, which are crucial processes for cell viability. Accordingly, antiporters are important drug targets in humans and underlie salt-resistance in plants. Many Na+/H+ antiporters are tightly regulated by pH. Escherichia coli NhaA Na+/H+ antiporter, a prototype pH-regulated antiporter, exchanges 2 H+for 1 Na+ (or Li+). The NhaA crystal structure has provided insights into the pH-regulated mechanism of antiporter action and opened up new in silico and in situavenues of research. The monomer is the functional unit of NhaA yet the dimer is essential for the stability of the antiporter under extreme stress conditions. Ionizable residues of NhaA that strongly interact electrostatically are organized in a transmembrane fashion in accordance with the functional organization of the cation-binding site, 'pH sensor', the pH transduction pathway and the pH-induced conformational changes. Remarkably, NhaA contains an inverted topology motive of transmembrane segments, which are interrupted by extended mid-membrane chains that have since been found to vary in other ion-transport proteins. This novel structural fold creates a delicately balanced electrostatic environment in the middle of the membrane, which might be essential for ion binding and translocation. Based on the crystal structure of NhaA, a model structure of the human Na+/H+ exchanger (NHE1) was constructed, paving the way to a rational drug design.
AB - Na+/H+ antiporters are integral membrane proteins that exchange Na+ for H+ across the cytoplasmic membrane and many intracellular membranes. They are essential for Na+, pH and volume homeostasis, which are crucial processes for cell viability. Accordingly, antiporters are important drug targets in humans and underlie salt-resistance in plants. Many Na+/H+ antiporters are tightly regulated by pH. Escherichia coli NhaA Na+/H+ antiporter, a prototype pH-regulated antiporter, exchanges 2 H+for 1 Na+ (or Li+). The NhaA crystal structure has provided insights into the pH-regulated mechanism of antiporter action and opened up new in silico and in situavenues of research. The monomer is the functional unit of NhaA yet the dimer is essential for the stability of the antiporter under extreme stress conditions. Ionizable residues of NhaA that strongly interact electrostatically are organized in a transmembrane fashion in accordance with the functional organization of the cation-binding site, 'pH sensor', the pH transduction pathway and the pH-induced conformational changes. Remarkably, NhaA contains an inverted topology motive of transmembrane segments, which are interrupted by extended mid-membrane chains that have since been found to vary in other ion-transport proteins. This novel structural fold creates a delicately balanced electrostatic environment in the middle of the membrane, which might be essential for ion binding and translocation. Based on the crystal structure of NhaA, a model structure of the human Na+/H+ exchanger (NHE1) was constructed, paving the way to a rational drug design.
KW - Active transport
KW - Membrane proteins
KW - Na+/H+ antiporters
KW - NHA
KW - NhaA
KW - NHE
UR - http://www.scopus.com/inward/record.url?scp=59149095664&partnerID=8YFLogxK
U2 - 10.1242/jeb.026708
DO - 10.1242/jeb.026708
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C2 - 19448069
AN - SCOPUS:59149095664
SN - 0022-0949
VL - 212
SP - 1593
EP - 1603
JO - Journal of Experimental Biology
JF - Journal of Experimental Biology
IS - 11
ER -