Structural basis of dual Ca²⁺/pH regulation of the endolysosomal TRPML1 channel.

ABSTRACT: The activities of organellar ion channels are often regulated by Ca²⁺ and H⁺, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca²⁺/pH regulation of TRPML1, a Ca²⁺-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architectur

SUBMITTER: Li M 

PROVIDER: S-EPMC5336481 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature