Amino acid substitutions at rheostat positions in the Na⁺/taurocholate cotransporting polypeptide substrate channel have pleiotropic effects.

ABSTRACT: In the human Na⁺/taurocholate cotransporting polypeptide (NTCP), several non-synonymous SNPs are known to have positive or negative medical consequences, and hundreds more are "variants of unknown significance." One reason outcomes remain unknown is that computational predictions are not yet reliable. Such predictions are especially problematic for "rheostat" positions, where amino acid substitutions have widely varied outcomes. We previously predicted that NTCP contains multiple rheostat positions for substrate transport. To test this, we selected two positions that-by classical assumptions-would not be rheostat positions. Position G102 is highly conserved and buried deep in the substrate channel; as such, most substitutions are expected to be catastrophic. In contrast, positio

SUBMITTER: Swint-Kruse L 

PROVIDER: S-EPMC12521614 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature