8JZS

Outward-facing SLC15A4 dimer

Summary for 8JZS

• Entry DOI: 10.2210/pdb8jzs/pdb
• EMDB information: 36752
• Descriptor: lysosomal transporter, 2-acetamido-2-deoxy-beta-D-glucopyranose, CHOLESTEROL (3 entities in total)
• Functional Keywords: endolysosomal transporter, protein transport
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 134456.31

Authors

Zhang, S.S.,Chen, X.D.,Xie, M. (deposition date: 2023-07-06, release date: 2023-09-27, Last modification date: 2023-12-13)

Primary citation

Chen, X.,Xie, M.,Zhang, S.,Monguio-Tortajada, M.,Yin, J.,Liu, C.,Zhang, Y.,Delacretaz, M.,Song, M.,Wang, Y.,Dong, L.,Ding, Q.,Zhou, B.,Tian, X.,Deng, H.,Xu, L.,Liu, X.,Yang, Z.,Chang, Q.,Na, J.,Zeng, W.,Superti-Furga, G.,Rebsamen, M.,Yang, M.
Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
Nat Commun, 14:6627-6627, 2023

PubMed Abstract: Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

PubMed: 37863913
DOI: 10.1038/s41467-023-42210-9

Experimental method

ELECTRON MICROSCOPY (2.95 Å)