4.5 Article

PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane

Journal

NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 11, Issue 1, Pages 36-44

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb709

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Funding

  1. NIGMS NIH HHS [GM 56827] Funding Source: Medline
  2. NIMH NIH HHS [MH61876] Funding Source: Medline
  3. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM056827] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH061876] Funding Source: NIH RePORTER

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Synaptotagmin-1 (syt), the putative Ca2+ sensor for exocytosis, is anchored to the membrane of secretory organelles. Its cytoplasmic domain is composed of two Ca2+-sensing modules, C(2)A and C2B. Syt binds phosphatidylinositol 4,5-bisphosphate (PIP2), a plasma membrane lipid with an essential role in exocytosis and endocytosis. We resolved two modes of PIP2 binding that are mediated by distinct surfaces on the C2B domain of syt. A novel Ca2+-independent mode of binding predisposes syt to penetrate PIP2-harboring target membranes in response to Ca2+ with submillisecond kinetics. Thus, PIP2 increases the speed of response of syt and steers its membrane-penetration activity toward the plasma membrane. We propose that syt-PIP2 interactions are involved in exocytosis by facilitating the close apposition of the vesicle and target membrane on rapid time scales in response to Ca2+.

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