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Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts
78
46-POS
Board 46
Potential Function and Prevalence of Intra/Inter-Protein Carboxylic-Acid Dimers
Gordon Wells
1
, Hongjie Yuan
2
, Scott Myers
2
, Yesim Tahirovic
3
, David Menaldino
3
, Thota
Ganesh
3
, James Snyder
3
, Dennis Liotta
3
, Stephen Traynelis
2
.
1
University of Stellenbosch, Stellenbosch, Western Cape, South Africa,
3
Emory University,
Atlanta, GA, USA.
2
Emory University, Atlanta, GA, USA,
The
N
-methyl-D-aspartate receptor (NMDAR) is expressed in most neurons of the mammalian
CNS. However, overstimulation of NMDAR by its associated neurotransmitter glutamate often
results in cell-death. Ischemic brain injury sites are characterised by increased glutamate
concentrations and lowered pH due to poor CO
2
clearance. Thus site-specific NMDAR inhibitors
may augment current interventions for treating ischemia.
A recent study
1
describing context dependent inhibitors of the NMDAR implicated an intra-
protein carboxylic acid dimer as key to increased inhibition at lower pH. This pH dependent
activity is desirable at the site of ischemic brain tissue, as this potentially allows selective
reduction of NMDAR induced neurotoxicity at the injury site, while minimizing off-target
effects in healthy tissue. Comparison of protein crystal structures solved at different pH values
revealed a pair of glutamate residues adopting a geometry consistent with a neutral carboxylic-
acid dimer at the lower pH. Subsequent mutagenesis of this pair reduced pH dependent
inhibition, suggesting that the carboxylic-acid dimer functions as a pH sensor.
This prompted a search for other dimers within the Protein Data Bank (PDB). A further 40 plus
proteins were found with Asp/Glu pairs adopting a geometry consistent with a carboxylic-acid
dimer. Approximately half of these interactions are mediated via metal chelation, with no nearby
metals apparent for the rest. The carboxylic-acid dimers are found in both solvent exposed and
buried locations in a wide variety of proteins.
Carboxylic acid dimers therefore represent a hitherto unrecognised intra/inter-protein interaction
that may be functionally significant. Furthermore, pH sensitivity highlights the potential for
exploiting drug targets that may only present themselves during the altered physiological
conditions induced by communicable diseases (e.g. severe malaria induced acidosis)
1
http://dx.doi.org/10.1016/j.neuron.2015.02.008