CLSTN3
Domain
The cytoplasmic domain binds synaptic Ca(2+).
Function
Postsynaptic adhesion molecule that binds to presynaptic neurexins to mediate both excitatory and inhibitory synapse formation (PubMed:25352602). Promotes synapse development by acting as a cell adhesion molecule at the postsynaptic membrane, which associates with both neurexin-alpha and neurexin-beta proteins at the presynaptic membrane (PubMed:25352602). Regulates the balance between excitatory and inhibitory synapses by inhibiting formation of excitatory parallel-fiber synapses and promoting formation of inhibitory synapses in the same neuron (By similarity). May also be involved in ascorbate (vitamin C) uptake via its interaction with SLC23A2/SVCT2 (PubMed:34673103). Complex formation with APBA2 and APP, stabilizes APP metabolism and enhances APBA2-mediated suppression of beta-APP40 secretion, due to the retardation of intracellular APP maturation (Probable) (PubMed:12972431).
Isoform CLSTN3beta
Adipose-specific isoform that plays a key role in adaptive thermogenesis. Facilitates the efficient use of stored triglyceride by promoting multilocular morphology of thermogenic adipocytes: acts by inhibiting the activity of CIDEA and CIDEC on lipid droplets, thereby preventing lipid droplet fusion and facilitating lipid utilization. May also participate in adaptive thermogenesis by promoting sympathetic innervation of thermogenic adipose tissue: acts by driving secretion of neurotrophic factor S100B from brown adipocytes, stimulating neurite outgrowth from sympathetic neurons.
Post-translational modifications
Proteolytically processed under normal cellular conditions (PubMed:15037614). A primary zeta-cleavage generates a large extracellular (soluble) N-terminal domain (sAlc) and a short C-terminal transmembrane fragment (CTF1) (PubMed:15037614). A secondary cleavage catalyzed by gamma-secretase within the transmembrane domain releases the beta-Alc-beta chain in the extracellular milieu and produces an intracellular fragment (AlcICD) (PubMed:15037614). This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with gamma-secretase (PubMed:15037614).
Isoform CLSTN3beta
Ubiquitinated: endoplasmic reticulum-localized protein is ubiquitinated and degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway.
Sequence Similarities
Belongs to the calsyntenin family.
Tissue Specificity
According to PubMed:12498782, expressed predominantly in the brain and in kidney (PubMed:12498782). Low levels in heart, skeletal muscle, liver, placenta, pancreas and lung (PubMed:12498782). According to PubMed:12972431, predominant expression in brain, and only marginal in kidney (PubMed:12972431). In brain, present throughout all cortical layers, highest levels in GABAergic neurons (based on morphology and distribution pattern) (PubMed:12972431).
Isoform CLSTN3beta
Expression is restricted to adipose tissue, with high expression in multilocular thermogenic adipocytes (brown adipose tissue).
Cellular localization
- Postsynaptic cell membrane
- Single-pass type I membrane protein
- Endoplasmic reticulum membrane
- Single-pass type I membrane protein
- Golgi apparatus membrane
- Single-pass type I membrane protein
- Cell projection
- Dendrite
- Most prominent in the postsynaptic specializations of asymmetric (type I) synapses with both axodendritic and axospinous localization.
- Isoform CLSTN3beta
- Lipid droplet
- Endoplasmic reticulum membrane
- Single-pass membrane protein
- Localizes to endoplasmic reticulum-lipid droplet contact sites through the partitioning of its N-terminal hydrophobic hairpins onto lipid droplets while its C-terminal transmembrane domain remains anchored in the endoplasmic reticulum.
Alternative names
CS3, KIAA0726, CLSTN3, Calsyntenin-3, Alcadein-beta, Alc-beta