Abstract
The DEG/ENaC (Degenerin/Epithelial Sodium Channel) protein family comprises related ion channel subunits from all metazoans, including humans. Members of this protein family play roles in several important biological processes such as transduction of mechanical stimuli, sodium re-absorption and blood pressure regulation. Several blocks of amino acid sequence are conserved in DEG/ENaC proteins, but structure/function relations in this channel class are poorly understood. Given the considerable experimental limitations associated with the crystallization of integral membrane proteins, knowledge-based modeling is often the only route towards obtaining reliable structural information. To gain insight into the structural characteristics of DEG/ENaC ion channels, we derived three-dimensional models of MEC-4 and UNC-8, based on the available crystal structures of ASIC1 (Acid Sensing Ion Channel 1). MEC-4 and UNC-8 are two DEG/ENaC family members involved in mechanosensation and proprioception respectively, in the nematode Caenorhabditis elegans. We used these models to examine the structural effects of specific mutations that alter channel function in vivo. The trimeric MEC-4 model provides insight into the mechanism by which gain-of-function mutations cause structural alterations that result in increased channel permeability, which trigger cell degeneration. Our analysis provides an introductory framework to further investigate the multimeric organization of the DEG/ENaC ion channel complex.
Highlights
The DEG/ENaC family of ion channels is a large group of proteins sharing a high degree of sequence and overall primary structure similarity
Four models of MEC-4 and four models UNC-8 subunits were obtained based on the 3 subunit structures of the homo-trimeric, closed acid sensing ion channel (ASIC1) of chicken (PDB ID: 2QTS; [9]) and on the one subunit structure of the minimal function construct of the same channel and organism (PDB ID: 3HGC; [8])
Structures comprising all visible residues have been used for modeling the MEC-4 and UNC-8 subunits A, B, C and H
Summary
The DEG/ENaC family of ion channels is a large group of proteins sharing a high degree of sequence and overall primary structure similarity. Four models of MEC-4 and four models UNC-8 subunits were obtained based on the 3 subunit structures of the homo-trimeric, closed acid sensing ion channel (ASIC1) of chicken (PDB ID: 2QTS; [9]) and on the one subunit structure of the minimal function construct of the same channel and organism (PDB ID: 3HGC; [8]).
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