PMID- 31053155
OWN - NLM
STAT- MEDLINE
DCOM- 20200526
LR  - 20200526
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 12
IP  - 1
DP  - 2019 May 3
TI  - SGIP1alpha functions as a selective endocytic adaptor for the internalization of 
      synaptotagmin 1 at synapses.
PG  - 41
LID - 10.1186/s13041-019-0464-1 [doi]
LID - 41
AB  - Proper sorting of exocytosed synaptic vesicle (SV) proteins into individual SVs 
      during endocytosis is of the utmost importance for the fidelity of subsequent 
      neurotransmission. Recent studies suggest that each SV protein is sorted into 
      individual SVs by its own dedicated adaptors as well as by association between SV 
      proteins. The SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), 
      an ortholog of Fer/Cip4 homology domain-only (FCHo) proteins, contains a 
      mu-homology domain (muHD) and binds AP-2 and Eps15, thus functioning as an 
      endocytic regulator of clathrin-mediated endocytosis (CME). Its longest isoform 
      SGIP1alpha is predominantly expressed in the brain but the functional significance of 
      SGIP1 in SV recycling remains unknown. Here, we found that SGIP1alpha, a 
      brain-specific long isoform of SGIP1 binds synaptotagmin1 (Syt1) via its muHD and 
      promotes the internalization of Syt1 on the neuronal surface. The small hairpin 
      RNA (shRNA)-mediated knockdown (KD) of SGIP1alpha caused selective impairment of Syt1 
      internalization at hippocampal synapses and it was fully rescued by coexpression 
      of the shRNA-resistant form of SGIP1alpha in KD neurons. We further found that the 
      muHD of SGIP1alpha is structurally similar to those of AP-2 and stonin2, and mutations 
      at Trp771 and Lys781, which correspond to Syt1-recognition motifs of AP-2 and 
      stonin2, to Ala bound less efficiently to Syt1 and failed to rescue the endocytic 
      defect of Syt1 caused by KD. Our results indicate that SGIP1alpha is an endocytic 
      adaptor dedicated to the retrieval of surface-stranded Syt1. Since endocytic 
      sorting of Syt1 is also mediated by the overlapping activities of synaptic 
      vesicle glycoprotein 2A/B (SV2A/B) and stonin2, our results suggest that 
      complementary fail-safe mechanism by these proteins ensures high fidelity of Syt1 
      retrieval.
FAU - Lee, Sang-Eun
AU  - Lee SE
AD  - Department of Physiology and Biomedical Sciences, Neuroscience Research 
      Institute, Seoul National University College of Medicine, Seoul, 03080, South 
      Korea.
FAU - Jeong, Soomin
AU  - Jeong S
AD  - Department of Physiology and Biomedical Sciences, Neuroscience Research 
      Institute, Seoul National University College of Medicine, Seoul, 03080, South 
      Korea.
FAU - Lee, Unghwi
AU  - Lee U
AD  - Department of Physiology and Biomedical Sciences, Neuroscience Research 
      Institute, Seoul National University College of Medicine, Seoul, 03080, South 
      Korea.
FAU - Chang, Sunghoe
AU  - Chang S
AD  - Department of Physiology and Biomedical Sciences, Neuroscience Research 
      Institute, Seoul National University College of Medicine, Seoul, 03080, South 
      Korea. sunghoe@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190503
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - 0 (Adaptor Protein Complex 2)
RN  - 0 (Adaptor Protein Complex mu Subunits)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Mutant Proteins)
RN  - 0 (SGIP1 protein, mouse)
RN  - 0 (Synaptophysin)
RN  - 0 (Synaptotagmin I)
RN  - 0 (Vesicle-Associated Membrane Protein 2)
RN  - 0 (adaptor protein complex 2, mu 2 subunit)
RN  - 0 (stonin 2 protein, mouse)
SB  - IM
MH  - Adaptor Protein Complex 2/metabolism
MH  - Adaptor Protein Complex mu Subunits/metabolism
MH  - Adaptor Proteins, Signal Transducing/chemistry/*metabolism
MH  - Adaptor Proteins, Vesicular Transport/metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - *Endocytosis
MH  - HEK293 Cells
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Mutant Proteins/metabolism
MH  - Neurons/metabolism
MH  - Presynaptic Terminals/metabolism
MH  - Protein Binding
MH  - Rats, Sprague-Dawley
MH  - Synapses/*metabolism
MH  - Synaptophysin/metabolism
MH  - Synaptotagmin I/*metabolism
MH  - Vesicle-Associated Membrane Protein 2/metabolism
PMC - PMC6499997
OTO - NOTNLM
OT  - Clathrin-mediated endocytosis
OT  - SGIP1alpha
OT  - Synaptic vesicle
OT  - synaptotagmin 1
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All of the animal experiments were 
      performed in accordance with the guidelines set by the Institute of Animal Care 
      and Use Committee (IACUC) of Seoul National University, Korea. CONSENT FOR 
      PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they 
      have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral 
      with regard to jurisdictional claims in published maps and institutional 
      affiliations.
EDAT- 2019/05/06 06:00
MHDA- 2020/05/27 06:00
PMCR- 2019/05/03
CRDT- 2019/05/05 06:00
PHST- 2019/03/07 00:00 [received]
PHST- 2019/04/16 00:00 [accepted]
PHST- 2019/05/05 06:00 [entrez]
PHST- 2019/05/06 06:00 [pubmed]
PHST- 2020/05/27 06:00 [medline]
PHST- 2019/05/03 00:00 [pmc-release]
AID - 10.1186/s13041-019-0464-1 [pii]
AID - 464 [pii]
AID - 10.1186/s13041-019-0464-1 [doi]
PST - epublish
SO  - Mol Brain. 2019 May 3;12(1):41. doi: 10.1186/s13041-019-0464-1.