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TitleStructural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 6157, Year 2023
Publish dateOct 3, 2023
AuthorsYishuo Lu / Peng Zuo / Hongyi Chen / Hui Shan / Weize Wang / Zonglin Dai / He Xu / Yayu Chen / Ling Liang / Dian Ding / Yan Jin / Yuxin Yin /
PubMed AbstractBTR1 (SLC4A11) is a NH stimulated H (OH) transporter belonging to the SLC4 family. Dysfunction of BTR1 leads to diseases such as congenital hereditary endothelial dystrophy (CHED) and Fuchs ...BTR1 (SLC4A11) is a NH stimulated H (OH) transporter belonging to the SLC4 family. Dysfunction of BTR1 leads to diseases such as congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy (FECD). However, the mechanistic basis of BTR1 activation by alkaline pH, transport activity regulation and pathogenic mutations remains elusive. Here, we present cryo-EM structures of human BTR1 in the outward-facing state in complex with its activating ligands PIP and the inward-facing state with the pathogenic R125H mutation. We reveal that PIP binds at the interface between the transmembrane domain and the N-terminal cytosolic domain of BTR1. Disruption of either the PIP binding site or protonation of PIP phosphate groups by acidic pH can transform BTR1 into an inward-facing conformation. Our results provide insights into the mechanisms of how the transport activity and conformation changes of BTR1 are regulated by PIP binding and interaction of TMD and NTD.
External linksNat Commun / PubMed:37788993 / PubMed Central
MethodsEM (single particle)
Resolution2.84 - 2.96 Å
Structure data

32940

7x1g

EMDB-32940, PDB-7x1g:
Cryo-EM structure of human BTR1 in the inward-facing state at pH 5.5
Method: EM (single particle) / Resolution: 2.94 Å

32941

7x1h

EMDB-32941, PDB-7x1h:
Cryo-EM structure of human BTR1 in the inward-facing state with R125H mutation
Method: EM (single particle) / Resolution: 2.96 Å

32942

7x1i

EMDB-32942, PDB-7x1i:
Cryo-EM structure of human BTR1 in the outward-facing state.
Method: EM (single particle) / Resolution: 2.94 Å

32943

7x1j

EMDB-32943, PDB-7x1j:
Cryo-EM structure of human BTR1 in the outward-facing state in the presence of NH4Cl.
Method: EM (single particle) / Resolution: 2.84 Å

Chemicals

ChemComp-PT5:
[(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho / phospholipid*YM / Phosphatidylinositol 4,5-bisphosphate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / SLC4A11 / BTR1 / SLC transporter

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