9dvp

Structure of the phosphate exporter XPR1/SLC53A1, Pi and InsP8-bound, intracellular gate closed state

spinqualitylabelsall models 9dvp, resolution 2.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9dvp is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.81Å Ligands: CLR, CPL, I8P, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease S53A1_HUMAN Bilateral striopallidodentate calcinosis. The disease is caused by variants affecting the gene represented in this entry. Function S53A1_HUMAN Inorganic ion transporter that mediates phosphate ion export across plasma membrane. Plays a major role in phosphate homeostasis, preventing intracellular phosphate accumulation and possible calcium phosphate precipitation, ultimately preserving calcium signaling. The molecular mechanism of phosphate transport, whether electrogenic, electroneutral or coupled to other ions, remains to be elucidated (By similarity) (PubMed:23791524, PubMed:25938945, PubMed:31043717). Binds inositol hexakisphosphate (Ins6P) and similar inositol polyphosphates, such as 5-diphospho-inositol pentakisphosphate (5-InsP7), important intracellular signaling molecules involved in regulation of phosphate flux (PubMed:27080106).[UniProtKB:Q9Z0U0] Publication Abstract from PubMed Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for cellular Pi homeostasis. When intercellular Pi is high, cells accumulate inositol pyrophosphate (1,5-InsP(8)), a signaling molecule required for XPR1 function. Inactivating XPR1 mutations lead to brain calcifications, causing neurological symptoms including movement disorders, psychosis, and dementia. Here, cryo-electron microscopy structures of dimeric XPR1 and functional characterization delineate the substrate translocation pathway and how InsP(8) initiates Pi transport. Binding of InsP(8) to XPR1, but not the related inositol polyphosphate InsP(6), rigidifies the intracellular SPX domains, with InsP(8) bridging the dimers and SPX and transmembrane domains. Locked in this state, the C-terminal tail is sequestered, revealing the entrance to the transport pathway, thus explaining the obligate roles of the SPX domain and InsP(8). Together, these findings advance our understanding of XPR1 transport activity and expand opportunities for rationalizing disease mechanisms and therapeutic intervention. , PMID:40113814 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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