BST1 protein (Bone Marrow Stromal Cell Antigen 1, also known as CD157 or ADP-ribosyl cyclase 2) is a GPI-anchored cell surface enzyme encoded by the BST1 gene. BST1 catalyzes the synthesis of cyclic ADP-ribose (cADPR) from NAD+, regulating intracellular calcium signaling. BST1 is expressed on immune cells, bone marrow stromal cells, and within the central nervous system. Genome-wide association studies have identified BST1 as a significant risk locus for Parkinson's disease, with risk variants potentially affecting microglial immune function and calcium homeostasis in the brain.
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| Protein Name | ADP-ribosyl cyclase 2 (CD157) |
| Gene | [BST1](/genes/bst1) |
| UniProt ID | [Q10588](https://www.uniprot.org/uniprot/Q10588) |
| PDB IDs | [1ISF](https://www.rcsb.org/structure/1ISF) |
| Molecular Weight | 33.9 kDa |
| Subcellular Localization | Cell surface (GPI-anchored), lipid rafts |
| Protein Family | ADP-ribosyl cyclase family (CD38/BST1) |
| Associated Diseases | [Parkinson's disease](/diseases/parkinsons-disease) |
¶ Domain Architecture
BST1 is a 318-amino acid GPI-anchored glycoprotein:
- Signal peptide (residues 1-26)
- Extracellular catalytic domain (residues 27-283): Contains the NAD+-binding cleft and ADP-ribosyl cyclase catalytic site; structurally homologous to CD38 (~33% sequence identity)
- GPI-anchor signal (residues 284-318): Cleaved and replaced by the GPI anchor for cell surface attachment
The enzymatic active site is located in a deep cleft within the extracellular domain:
- Key catalytic residues: Glu148 (catalytic glutamate), Trp171, Asp155
- NAD+ binding: NAD+ enters the active site cleft; BST1 cleaves the nicotinamide-ribose bond and cyclizes ADP-ribose to form cADPR
- Compared to CD38: BST1 has weaker cyclase activity but stronger NADase (hydrolase) activity, producing ADPR as the major product
¶ GPI Anchor and Lipid Raft Association
- The GPI anchor tethers BST1 to the outer leaflet of the plasma membrane
- BST1 partitions into cholesterol-rich lipid raft microdomains
- Lipid raft localization is important for signal transduction and receptor clustering
- BST1 can be released from the cell surface by GPI-specific phospholipase C or shed by metalloproteinases
BST1 catalyzes the conversion of NAD+ to cyclic ADP-ribose (cADPR):
- cADPR activates ryanodine receptors on the ER, releasing intracellular Ca2+
- This NAD+-calcium signaling axis regulates cell activation, proliferation, and chemotaxis
- BST1 also generates ADPR, which activates TRPM2 calcium channels
- In neurons, cADPR/ADPR signaling modulates synaptic transmission and plasticity
- Neutrophil migration: BST1 functions as a receptor for growth factor-primed neutrophil transendothelial migration
- Pre-B cell growth: BST1 was originally identified as a stromal cell factor supporting pre-B lymphocyte growth
- Monocyte/macrophage activation: BST1 engagement promotes inflammatory cytokine production
- Expressed in microglia, astrocytes, and neurons at low-moderate levels
- Microglial BST1 regulates calcium-dependent phagocytosis and inflammatory responses
- Neuronal BST1 contributes to calcium homeostasis and synaptic function
- NAD+ metabolism through BST1 intersects with SIRT1/SIRT2 sirtuin-dependent neuroprotection pathways
BST1 is a genome-wide significant PD risk locus identified in multiple GWAS:
- Lead SNP: rs4698412 (4p15.32, p < 5×10−8 in combined Asian and European populations)
- Risk mechanism: Risk alleles are associated with altered BST1 expression, potentially affecting microglial calcium signaling and NAD+ metabolism
- Microglial inflammation: Dysregulated BST1 activity may enhance microglial inflammatory responses through cADPR-mediated calcium mobilization
- NAD+ depletion: Excessive BST1 NADase activity could deplete neuronal NAD+ pools, impairing sirtuin-dependent mitochondrial quality control and PINK1/Parkin pathway function
- Dopaminergic vulnerability: Calcium dysregulation through BST1/TRPM2 signaling may increase susceptibility of substantia nigra dopaminergic neurons, which already have elevated calcium demands
- Immune-mediated neurodegeneration: BST1 risk variants may shift microglial phenotype toward pro-inflammatory activation, accelerating α-synuclein-driven neurodegeneration
¶ Connection to CD38 and NAD+ Biology
- BST1 and its paralog CD38 are the major NADases in mammals
- CD38 expression increases with age and inflammation, depleting NAD+ pools
- BST1 may similarly contribute to age-related NAD+ decline in the brain
- NAD+ supplementation strategies (NMN, NR) may counteract BST1/CD38-mediated NAD+ depletion
- BST1 inhibitors: Small molecules targeting the catalytic site could preserve NAD+ pools and reduce cADPR-mediated inflammatory calcium signaling
- NAD+ supplementation: Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) restore NAD+ pools depleted by BST1/CD38
- CD38/BST1 dual inhibitors: 78c and apigenin inhibit both CD38 and BST1 NADase activity
- Anti-BST1 antibodies: Potential for modulating microglial inflammatory responses