Regulation of Caenorhabditis elegans degenerin proteins by a putative extracellular domain.
BACKGROUND
Rare, dominant mutations in the degenerin genes of Caenorhabditis elegans (deg-1, mec-4 and mec-10) cause neuronal degeneration. The extensive sequence similarity between degenerins and mammalian genes that encode subunits of the amiloride-sensitive sodium channel from kidney, colon and lung suggests that the C. elegans degenerins form ion channels. As mec-4 and mec-10 are needed for the reception of gentle touch stimuli, they may contribute to a mechanosensory ion channel. All the dominant degeneration-causing mutations in the C. elegans degenerin genes affect equivalent residues in a hydrophobic region that is structurally similar to the H5 domain of several ion channels, and so could form the channel lining. Increased channel activity may underlie the resulting degeneration, in which the affected cells vacuolate and swell.


RESULTS
We now demonstrate that a missense change in a predicted extracellular region of the proteins encoded by deg-1 and mec-4 causes cell death similar to that caused by the dominant mutations. The missense mutation lies within a 22 amino-acid region found in all the C. elegans degenerins for which the sequences have been published, but not in the similar mammalian proteins. Deletion of nine amino acids surrounding the mutation site in mec-4 also causes neuronal degeneration. The degeneration-causing mutations in either the predicted pore-lining or the predicted extracellular regions of deg-1 are suppressed by additional, dominantly acting mutations that substitute larger for smaller residues within the channel lining.


CONCLUSIONS
Our data suggest that the putative extracellular domain negatively regulates degenerin activity, perhaps by gating the channel. As this region is only found in the C. elegans proteins, it may allow more rapid regulation of the nematode channels, which may be needed for them to function in mechanosensation. The suppressor mutations, by adding larger amino acids to the putative pore lining, could prevent degeneration by blocking the pore of a multisubunit channel.
García-Añoveros
J
J
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Ma
C
C
Chalfie
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D015222:Sodium Channels / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; C094927:Deg-1 protein, C elegans; D015801:Helminth Proteins; C115871:Mec-4 protein, C elegans; D008565:Membrane Proteins; D015222:Sodium Channels