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FLASH GENE

Symbol

SYT1

contributors: shn/npt/pgu - updated : 06-04-2022

HGNC name	synaptotagmin I
HGNC id	11509

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	NEDIMAE neurodevelopmental disorder with involuntary movements and abnormal electroencephalogram
Location	12q21.2      Physical location : 79.257.772 - 79.845.787
Synonym symbol(s)	SYT, SYTG1, P65, SVP65, DKFZp781D2042, FLJ37297, BRAMY2015503, BAGOS

DNA

TYPE	functioning gene
STRUCTURE	588.02 kb     12 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	cen - D12S350 - D12S326 - SYT1 - D12S106 - D12S1708 - qter
Authors	4st Workshop chrom.12 (97)

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001135805 12 splicing 4841 NP_001129277 - 422 neuron-specific 1995 7624059 NM_005639 11 splicing 4827 NP_005630 - 422 neuron-specific 1995 7624059 NM_001135806 10 splicing 4427 NP_001129278 - 422 neuron-specific 1995 7624059

EXPRESSION

Type	restricted

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine neuroendocrine pituitary     moderately Nervous brain forebrain cerebral cortex frontal highly   brain limbic system hippocampus   highly Mus musculus   brain hindbrain cerebellum   highly Mus musculus Reproductive female system breast mammary gland   moderately Visual eye retina       Mus musculus

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular       moderately

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an intravesicular N terminal domain
	a single transmembrane (TM) region
	two protein kinase C-homologous repeats (Ca2+ binding domains C2), C2A and C2B domains(the binding of Ca(2+) to the C2A domain activates the exocytosis of secretory vesicles, while the binding of inositol polyphosphates (IP4-IP6) to the C2B domain inhibits this process )
	a conserved WHXL motif in the C terminus

conjugated

GlycoP , LipoP

mono polymer

homomer , heteromer , tetramer , complex

HOMOLOGY

interspecies	ortholog to Syt1, Rattus norvegicus
	ortholog to Syt1, Mus musculus
	ortholog to SYT1, Pan troglodytes

Homologene

FAMILY

synaptotagmin family

CATEGORY

structural protein , transport

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic,granule
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus
text	membrane of synaptic vesicle
	chromaffin granules

basic FUNCTION	a calcium sensor on the synaptic vesicle surface
	acting as a calcium regulator of neurotransmitter release at the central synapse to initiate signal transduction
	Ca2+ sensor for fast synchronous neurotransmitter release in forebrain neurons and chromaffin cells
	involved in exocytosis and endocytosis, selectively required for the fast synchronous component of exocytosis, but not for the delayed, asynchronous component
	acting as a transcriptional coactivator with SNF/SWI complex characterized as a chromatin remodeling factor enhancing accessibility of the transcriptional machinery to DNA within a repressive chromatin structure
	mediating FGF1 release
	may have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse
	Ca2+ sensor for fast neurotransmitter release, functioning by Ca2+-dependent phospholipid binding and/or by Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex binding
	Ca(2+)-binding motif of the C(2)B domain of synaptotagmin 1 essential for synaptic transmission
	is necessary for the endocytosis of synaptic vesicles
	triggers the fusion of docked vesicles by local Ca2+-dependent buckling of the plasma membrane together with the zippering of SNAREs
	involved in neurite outgrowth, early neuronal cell development, neuropeptide signaling/synthesis and neuronal receptor
	Syt1 controls both evoked and spontaneous release of neurotransmitter quanta at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis
	modulates lipid acyl chain order in lipid bilayers by demixing phosphatidylserine
	functions as a dual Ca(2+) sensor for both endo- and exocytosis, potentially coupling these two components of the vesicle cycle
	importance of an asymmetric distribution of acidic lipids for synaptotagmin 1 function as a Ca2+ sensor
	may be a Ca2+ sensors for spontaneous release
	is necessary for the Ca++ dependence of clathrin-mediated endocytosis
	synaptic vesicle membrane protein that serves as a multifunctional regulator during the exocytosis of neurotransmitter release
	with SYT1, CPLX1 synchronizes and stimulates rapid fusion of accumulated docked vesicles in response to physiological Ca(2+) concentrations
	in neurotransmission SYT1 tethers synaptic vesicles to the presynaptic plasma membrane by binding to acidic membrane lipids and SNAREs and promotes rapid SNARE-mediated fusion upon Ca(2+) triggering
	vesicular protein interacting with membranes upon low-affinity Ca²&
	8314;-binding, and playing a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release
	is also involved in a rapid vesicular Ca²&
	8314; sequestration through a Ca²&
	8314;/H&
	8314; antiport
	SYT1 and SYT2 can redundantly control transmitter release at specific brain synapses
	SYT1, a Ca2+ sensor, mediates ultrafast exocytosis in neurons and neuroendocrine cells
	SYT1 mediates both phasic and tonic release at photoreceptor synapses, revealing unexpected flexibility in the ability of SYT1 to regulate Ca2+-dependent synaptic transmission
	Ca2+-sensitive SYT1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release
	role of the SYT1 protein involved in the secretory vesicle docking, priming, and fusion
	juxtamembrane linker of SYT1 plays a crucial role in exocytosis by mediating multimerization
	is a critical mediator of neurotransmitter release in the central nervous system
	key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function

CELLULAR PROCESS

cell communication

PHYSIOLOGICAL PROCESS

nervous system , exocytosis transport , endocytosis transport

text	Ca(2+) sensor in the process of vesicular trafficking and exocytosis

PATHWAY

metabolism

signaling

neurotransmission , signal transduction

a component	multifunctional intrinsic membrane protein of synaptic vesicles of neurons and chromaffin granules
	forming a complex with SV2B, syntaxin 1 and SNAP25

INTERACTION

DNA

RNA

small molecule	metal binding,
	Ca2+ (3 ions per subunit, via the C2 domain)

protein	transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha), TFAP2A
	syntaxin 1A, STX1A
	cytoplasmic domain of the alpha1A subunit of the P/Q-type calcium channel, CACNA1A
	S100 calcium binding protein A13, S100A13 (PMID :
	Fibroblast growth factor 1, FGF1
	regulating synaptic membrane exocytosis 1, RIMS1
	zinc finger, DHHC-type containing 17, ZDHHC17 also known as HIP14
	synaptic vesicle glycoprotein 2B, SV2B
	intestinal epithelial SYT1 plays an important role in cAMP-stimulated endocytosis of apical SLC9A3 through cAMP-dependent phosphorylation of S605 that is required for NHE3 and SYT1 association
	CPLX1, CPLX2 facilitate and inhibit neurotransmitter release through distinct domains, and their function was proposed to be coupled to the Ca(2+) sensor synaptotagmin-1 (SYT1)
	interplay between STXBP5 and SYT1 underlies inhibitory control of Ca2+-dependent neurotransmitter release
	binds SNARE complexes before Ca(2+) influx into presynaptic nerve terminals
	SYT1 acts as an antagonist for STXBP1 in SNARE zippering and fusion pore opening
	is a novel Ca(2+)-sensitive PSEN1 modulator that could regulate synaptic APP opening avenues for novel and selective synapse targeting therapeutic strategies
	SYT1 can suppress Store-operated calcium entry (SOCE)-mediated spontaneous release, and STIM2 is required for the increase in spontaneous release seen during SYT1 loss of function

cell & other

acidic phospholipids via the first C2 domain

REGULATION

repressed by

synaptic vesicle glycoprotein 2B, SV2B

ASSOCIATED DISORDERS

corresponding disease(s)

NEDIMAE

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with SSX1(C terminal region) in synovial sarcoma

Susceptibility

to Attention-Deficit/Hyperactivity Disorder (ADHD)

Variant & Polymorphism other	association between SYT1-rs2251214 and ADHD in adulthood, and child

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	deletions of Syt1 produce increases in spontaneous mini release in Drosophila neuromuscular junctions
	introduction by homologous recombination the endogenous synaptotagmin I gene with a point mutation in mice led to a decrease of the Ca2+ sensitivity of neurotransmitter release twofold
	in cultured cortical neurons stimulated at low frequency, deletion of synaptotagmin 1 blocks synchronous GABA and glutamate release without significantly increasing asynchronous release