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Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
Chen, Xudong; Xie, Min; Zhang, Sensen; Monguió-Tortajada, Marta; Yin, Jian; Liu, Chang; Zhang, Youqi; Delacrétaz, Maeva; Song, Mingyue; Wang, Yixue; Dong, Lin; Ding, Qiang; Zhou, Boda; Tian, Xiaolin; Deng, Haiteng; Xu, Lina; Liu, Xiaohui; Yang, Zi; Chang, Qing; Na, Jie; Zeng, Wenwen; Superti-Furga, Giulio; Rebsamen, Manuele; Yang, Maojun.
Affiliation
  • Chen X; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Xie M; School of Medicine, Tsinghua University, 100084, Beijing, China.
  • Zhang S; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Monguió-Tortajada M; Department of Immunobiology, University of Lausanne, 1066, Epalinges, Switzerland.
  • Yin J; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Liu C; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Zhang Y; Beijing Life Science Academy, 102209, Beijing, China.
  • Delacrétaz M; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, 100853,
  • Song M; Department of Immunobiology, University of Lausanne, 1066, Epalinges, Switzerland.
  • Wang Y; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Dong L; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Ding Q; Center for Infectious Disease Research, School of Medicine, Tsinghua University, 100084, Beijing, China.
  • Zhou B; Center for Infectious Disease Research, School of Medicine, Tsinghua University, 100084, Beijing, China.
  • Tian X; Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, 102218, Beijing, China.
  • Deng H; MOE Key laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Xu L; MOE Key laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Liu X; Metabolomics and Lipidomics Center at Tsinghua-National Protein Science Facility, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Yang Z; Metabolomics and Lipidomics Center at Tsinghua-National Protein Science Facility, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Chang Q; Beijing Advanced Innovation Center for Structural Biology, Technology for Protein Research, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Na J; Beijing Advanced Innovation Center for Structural Biology, Technology for Protein Research, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • Zeng W; School of Medicine, Tsinghua University, 100084, Beijing, China.
  • Superti-Furga G; School of Medicine, Tsinghua University, 100084, Beijing, China.
  • Rebsamen M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Yang M; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Nat Commun ; 14(1): 6627, 2023 10 20.
Article in En | MEDLINE | ID: mdl-37863913
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Toll-Like Receptors Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: China Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Toll-Like Receptors Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: China Country of publication: United kingdom