A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.

Hansson, Joni H.; Schild, Laurent; Lu, Yin; Wilson, Thomas A.; Gautschi, Ivan; Shimkets, Richard A.; Nelson‐Williams, Carol; Rossier, Bernard C.; Lifton, Richard P.

doi:10.1073/pnas.92.25.11495

Cited by 338 publications

(246 citation statements)

References 13 publications

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“…Mutation to a smaller Ala residue disrupts the stabilizing interactions between the aromatic ring of Tyr-618Ј and this pocket on the WW domain. In addition, Pro-616Ј and Tyr-618Ј were found mutated in Liddle's syndrome patients (12,13), underscoring their physiological significance.…”

Section: Figmentioning

confidence: 99%

Affinity and Specificity of Interactions between Nedd4 Isoforms and the Epithelial Na+ Channel

Henry

Kanelis

O'Brien

et al. 2003

Journal of Biological Chemistry

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The epithelial Na ؉ channel (␣␤␥ENaC) regulates salt and fluid homeostasis and blood pressure. Each ENaC subunit contains a PY motif (PPXY) that binds to the WW domains of Nedd4, a Hect family ubiquitin ligase containing 3-4 WW domains and usually a C2 domain. It has been proposed that Nedd4-2, but not Nedd4-1, isoforms can bind to and suppress ENaC activity. Here we challenge this notion and show that, instead, the presence of a unique WW domain (WW3*) in either Nedd4-2 or Nedd4-1 determines high affinity interactions and the ability to suppress ENaC. WW3* from either Nedd4-2 or Nedd4-1 binds ENaC-PY motifs equally well (e.g. K d ϳ10 M for ␣-or ␤ENaC, 3-6-fold higher affinity than WW4), as determined by intrinsic tryptophan fluorescence. Moreover, dNedd4-1, which naturally contains a WW3* instead of WW2, is able to suppress ENaC function equally well as Nedd4-2. Homology models of the WW3*⅐␤ENaC-PY complex revealed that a Pro and Ala conserved in all WW3*, but not other Nedd4-WW domains, help form the binding pocket for PY motif prolines. Extensive contacts are formed between the ␤ENaC-PY motif and the Pro in WW3*, and the small Ala creates a large pocket to accommodate the peptide. Indeed, mutating the conserved Pro and Ala in WW3* reduces binding affinity 2-3-fold. Additionally, we demonstrate that mutations in PY motif residues that form contacts with the WW domain based on our previously solved structure either abolish or severely reduce binding affinity to the WW domain and that the extent of binding correlates with the level of ENaC suppression. Independently, we show that a peptide encompassing the PY motif of sgk1, previously proposed to bind to Nedd4-2 and alter its ability to regulate ENaC, does not bind (or binds poorly) the WW domains of Nedd4-2. Collectively, these results suggest that high affinity of WW domain-PY-motif interactions rather than affiliation with Nedd4-1/Nedd-2 is critical for ENaC suppression by Nedd4 proteins.

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Section: Figmentioning

confidence: 99%

Affinity and Specificity of Interactions between Nedd4 Isoforms and the Epithelial Na+ Channel

Henry

Kanelis

O'Brien

et al. 2003

Journal of Biological Chemistry

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“…Therefore, ENaC is critical for regulation of sodium balance and circulating volume (4,(7)(8)(9)(10). The physiological importance of ENaC to regulation of blood pressure in humans is emphasized by inheritable forms of hypertension (Liddle syndrome) resulting from gain-of-function mutations of the channel (5,9,(11)(12)(13)(14). Loss-of-function mutations, in contrast, lead to salt wasting and low blood pressure (pseudohypoaldosteronism type I) (9,13).…”

Section: Whereas Regulation Of Enac By Aldosterone Is Generally Accepmentioning

confidence: 99%

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Mamenko

Zaika

Ilatovskaya

et al. 2012

Journal of Biological Chemistry

132

123

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“…Targeted disruption of the β or γ subunits in mice produces a similar phenotype [10,11]. Conversely, in Liddle's syndrome mutations in the β or γ subunits cause severe high blood pressure [12][13][14]. Na + channels containing the Liddle's mutation expressed in itro show at least twice the activity of normal channels and the turnover rate of mutant channels appears to be decreased [15,16].…”

Section: Introductionmentioning

confidence: 99%

Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits

et al. 2000

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A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity.

Abstract: Liddle syndrome is a mendelian form of hypertension characterized by constitutively elevated renal Na reabsorption that can result from activating mutations in the 13 or y subunit of the epithelial Na channel. All reported

Cited by 338 publications

References 13 publications

Affinity and Specificity of Interactions between Nedd4 Isoforms and the Epithelial Na+ Channel

Affinity and Specificity of Interactions between Nedd4 Isoforms and the Epithelial Na+ Channel

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits

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