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Title: Role of gamma carboxylated Glu47 in connexin 26 hemichannel regulation by extracellular Ca{sup 2+}: Insight from a local quantum chemistry study

Graphical abstract: - Highlights: • QM calculations show that Ca{sup 2+} binds to γGlu47 in connexin hemichannels. • Molecular models of increasing size are employed in hybrid DFT calculations. • Ca{sup 2+} binding affects the interaction between γGlu47 and Arg75, Arg184. • Ca{sup 2+} binding alters the structure in a critical region of connexin hemichannels. - Abstract: Connexin hemichannels are regulated by several gating mechanisms, some of which depend critically on the extracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub e}). It is well established that hemichannel activity is inhibited at normal (∼1 mM) [Ca{sup 2+}]{sub e}, whereas lowering [Ca{sup 2+}]{sub e} to micromolar levels fosters hemichannel opening. Atomic force microscopy imaging shows significant and reversible changes of pore diameter at the extracellular mouth of Cx26 hemichannels exposed to different [Ca{sup 2+}]{sub e}, however, the underlying molecular mechanisms are not fully elucidated. Analysis of the crystal structure of connexin 26 (Cx26) gap junction channels, corroborated by molecular dynamics (MD) simulations, suggests that several negatively charged amino acids create a favorable environment for low-affinity Ca{sup 2+} binding within the extracellular vestibule of the Cx26 hemichannel. In particular a highly conserved glutammic acid, found in position 47 in most connexins, is thought to undergomore » post translational gamma carboxylation (γGlu47), and is thus likely to play an important role in Ca{sup 2+} coordination. γGlu47 may also form salt bridges with two conserved arginines (Arg75 and Arg184 in Cx26), which are considered important in stabilizing the structure of the extracellular region. Using a combination of quantum chemistry methods, we analyzed the interaction between γGlu47, Arg75 and Arg184 in a Cx26 hemichannel model both in the absence and in the presence of Ca{sup 2+}. We show that Ca{sup 2+} imparts significant local structural changes and speculate that these modifications may alter the structure of the extracellular loops in Cx26, and may thus account for the mechanism of hemichannel closure in the presence of mM [Ca{sup 2+}]{sub e}.« less
Authors:
 [1] ;  [1] ;  [2] ;  [2] ; ;  [3] ;  [3] ;  [3]
  1. Dipartimento di Fisica e Astronomia “G. Galilei”, Università degli Studi di Padova, 35131 Padova (Italy)
  2. (Italy)
  3. Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, 35131 Padova (Italy)
Publication Date:
OSTI Identifier:
22416287
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 445; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AFFINITY; ARGININE; ATOMIC FORCE MICROSCOPY; CALCIUM IONS; CARBOXYLATION; CHEMISTRY; CONCENTRATION RATIO; CRYSTAL STRUCTURE; DISEASES; HYBRIDIZATION; JOINTS; MOLECULAR DYNAMICS METHOD; MOLECULAR MODELS; MUTATIONS; SALTS