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<p>Synaptotagmins (Syts) are the primary Ca<sup>2+</sup>-sensors for synaptic vesicle exocytosis, while most mammalian Syts are non-Ca<sup>2+</sup>-affinitive and play critical roles in neurotransmission and synaptic plasticity with unclear mechanisms. Here, we show that high-alkaline non-Ca<sup>2+</sup>-binding Syt11 exhibits higher affinity for acidic phospholipids and Ca<sup>2+</sup>-inhibited liposome-binding, thereby competing with the Ca<sup>2+</sup>-binding Syt1. Physiological levels of Ca<sup>2+</sup> eliminate this competition by promoting Ca<sup>2+</sup>-dependent membrane insertion of Syt1 while suppressing Syt11’s binding through electrostatic shielding of the membrane surface. Site-directed mutagenesis reveals a dual-regional lipid-binding mode (a lysine-rich motif for Ca<sup>2+</sup>-independent binding and Ca<sup>2+</sup>-binding loops for Ca<sup>2+</sup>-facilitation) for Syt1, and a redundant multi-point lipid-binding interface for Syt11. Consistent with the Ca<sup>2+</sup>-dependent competition, Syt11 inhibits both the early stages of exocytosis and endocytosis in neurons, while the maximal rate of exocytosis remains intact. This Ca<sup>2+</sup>-sensitivity of Syt11 proposes Syt1-Syt11 inter-switching in membrane-occupancy as a critical step precisely controlling exocytosis and endocytosis during synaptic transmission.</p>

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Calcium-sensitive synaptotagmin 11-lipid interaction modulates exo-endocytosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月16日

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  • Xuanang Wu,
  • Jingyu Yao,
  • Jingxiao Huo,
  • Shaoqin Hu,
  • Bianbian Wang,
  • Ziyang Li,
  • Yingmei Pei,
  • Hong Fan,
  • Shuqin Zhan,
  • Rong Huang,
  • Xinjiang Kang,
  • Cong Ma,
  • Ying Lai,
  • Jing Han,
  • Lianying Jiao,
  • Qian Song,
  • Changhe Wang,
  • Huadong Xu

摘要

Synaptotagmins (Syts) are the primary Ca2+-sensors for synaptic vesicle exocytosis, while most mammalian Syts are non-Ca2+-affinitive and play critical roles in neurotransmission and synaptic plasticity with unclear mechanisms. Here, we show that high-alkaline non-Ca2+-binding Syt11 exhibits higher affinity for acidic phospholipids and Ca2+-inhibited liposome-binding, thereby competing with the Ca2+-binding Syt1. Physiological levels of Ca2+ eliminate this competition by promoting Ca2+-dependent membrane insertion of Syt1 while suppressing Syt11’s binding through electrostatic shielding of the membrane surface. Site-directed mutagenesis reveals a dual-regional lipid-binding mode (a lysine-rich motif for Ca2+-independent binding and Ca2+-binding loops for Ca2+-facilitation) for Syt1, and a redundant multi-point lipid-binding interface for Syt11. Consistent with the Ca2+-dependent competition, Syt11 inhibits both the early stages of exocytosis and endocytosis in neurons, while the maximal rate of exocytosis remains intact. This Ca2+-sensitivity of Syt11 proposes Syt1-Syt11 inter-switching in membrane-occupancy as a critical step precisely controlling exocytosis and endocytosis during synaptic transmission.