TY - JOUR
T1 - PI(4,5)P2-dependent regulation of exocytosis by amisyn, the vertebrate-specific competitor of synaptobrevin 2
AU - Kondratiuk, Ilona
AU - Jakhanwal, Shrutee
AU - Jin, Jialin
AU - Sathyanarayanan, Udhayabhaskar
AU - Kroppen, Benjamin
AU - Pobbati, Ajaybabu V.
AU - Krisko, Anita
AU - Ashery, Uri
AU - Meinecke, Michael
AU - Jahn, Reinhard
AU - Fasshauer, Dirk
AU - Milosevic, Ira
N1 - Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/16
Y1 - 2020/6/16
N2 - The functions of nervous and neuroendocrine systems rely on fast and tightly regulated release of neurotransmitters stored in secretory vesicles through SNARE-mediated exocytosis. Few proteins, including tomosyn (STXBP5) and amisyn (STXBP6), were proposed to negatively regulate exocytosis. Little is known about amisyn, a 24-kDa brain-enriched protein with a SNARE motif. We report here that full-length amisyn forms a stable SNARE complex with syntaxin-1 and SNAP-25 through its C-terminal SNARE motif and competes with synaptobrevin-2/VAMP2 for the SNAREcomplex assembly. Furthermore, amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane of neurosecretory cells by binding to phospholipid PI(4,5)P2. However, unlike synaptrobrevin-2, the SNARE motif of amisyn is not sufficient to account for the role of amisyn in exocytosis: Both the pleckstrin homology domain and the SNARE motif are needed for its inhibitory function. Mechanistically, amisyn interferes with the priming of secretory vesicles and the sizes of releasable vesicle pools, but not vesicle fusion properties. Our biochemical and functional analyses of this vertebrate-specific protein unveil key aspects of negative regulation of exocytosis.
AB - The functions of nervous and neuroendocrine systems rely on fast and tightly regulated release of neurotransmitters stored in secretory vesicles through SNARE-mediated exocytosis. Few proteins, including tomosyn (STXBP5) and amisyn (STXBP6), were proposed to negatively regulate exocytosis. Little is known about amisyn, a 24-kDa brain-enriched protein with a SNARE motif. We report here that full-length amisyn forms a stable SNARE complex with syntaxin-1 and SNAP-25 through its C-terminal SNARE motif and competes with synaptobrevin-2/VAMP2 for the SNAREcomplex assembly. Furthermore, amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane of neurosecretory cells by binding to phospholipid PI(4,5)P2. However, unlike synaptrobrevin-2, the SNARE motif of amisyn is not sufficient to account for the role of amisyn in exocytosis: Both the pleckstrin homology domain and the SNARE motif are needed for its inhibitory function. Mechanistically, amisyn interferes with the priming of secretory vesicles and the sizes of releasable vesicle pools, but not vesicle fusion properties. Our biochemical and functional analyses of this vertebrate-specific protein unveil key aspects of negative regulation of exocytosis.
KW - Autism spectrum disorders
KW - Exocytosis inhibition
KW - PI(4,5)P2
KW - SNARE complex
KW - Tomosyn
UR - http://www.scopus.com/inward/record.url?scp=85086682827&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1908232117
DO - https://doi.org/10.1073/pnas.1908232117
M3 - مقالة
C2 - 32467162
SN - 0027-8424
VL - 117
SP - 13468
EP - 13479
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -