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J Biol Chem
2018 Nov 09;29345:17582-17592. doi: 10.1074/jbc.RA118.003618.
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Thumb domains of the three epithelial Na+ channel subunits have distinct functions.
Sheng S
,
Chen J
,
Mukherjee A
,
Yates ME
,
Buck TM
,
Brodsky JL
,
Tolino MA
,
Hughey RP
,
Kleyman TR
.
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The epithelial Na+ channel (ENaC) possesses a large extracellular domain formed by a β-strand core enclosed by three peripheral α-helical subdomains, which have been dubbed thumb, finger, and knuckle. Here we asked whether the ENaC thumb domains play specific roles in channel function. To this end, we examined the characteristics of channels lacking a thumb domain in an individual ENaC subunit (α, β, or γ). Removing the γ subunit thumb domain had no effect on Na+ currents when expressed in Xenopus oocytes, but moderately reduced channel surface expression. In contrast, ENaCs lacking the α or β subunit thumb domain exhibited significantly reduced Na+ currents along with a large reduction in channel surface expression. Moreover, channels lacking an α or γ thumb domain exhibited a diminished Na+ self-inhibition response, whereas this response was retained in channels lacking a β thumb domain. In turn, deletion of the α thumb domain had no effect on the degradation rate of the immature α subunit as assessed by cycloheximide chase analysis. However, accelerated degradation of the immature β subunit and mature γ subunit was observed when the β or γ thumb domain was deleted, respectively. Our results suggest that the thumb domains in each ENaC subunit are required for optimal surface expression in oocytes and that the α and γ thumb domains both have important roles in the channel's inhibitory response to external Na+ Our findings support the notion that the extracellular helical domains serve as functional modules that regulate ENaC biogenesis and activity.
Figure 1. Thumb domains in monomeric and trimeric ASIC1 models. A, a monomer ASIC1 structural model
is shown as ribbons with individual domains colored and labeled (TM, transmembrane domain). Seven
disulfide bridges are numbered and displayed as space-filled spheres. The beginnings and ends of the two
sets of thumb domain deletions are identified by a red knife and a black arrow head. B, a trimeric ASIC1
model is shown as three colored ribbons with the deletion targets as surface rendering. Both monomeric
and trimeric ASIC1 models were built from the coordinates of the closed state structure of chicken ASIC1
(PDB Entry ID: 5WKV, (55)), using PyMol (59). C, sequence alignments showing the targeted residues in
the two sets of thumb domain deletions. Alignments were done with Vector NTI 11.0 (Invitrogen) with
manual adjustment from protein sequences with GenBank Accession Number AAD21244 (αmENaC),
AAD21245 (βmENaC), AAD21246 (γmENaC) and AY956393 (cASIC1). The first residue number in each
line of sequence is shown in parenthesis. Identical and conserved residues are shown in red letters on yellow
background and black letters on green background, respectively. The percentage of identical residues
between a mouse ENaC subunit and cASIC1 is 22-24 for the full length subunits and 17-24 for the thumb
domains alone. The black arrow head and red knife show the beginnings of two sets of thumb domain
deletion.
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