Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
Falcon deep research report for human PCSK1N
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PCSK1N encodes proSAAS, a regulated-secretory-pathway precursor and endogenous PC1/3 inhibitor that modulates prohormone processing in secretory granules.
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The report also supports proSAAS as a secretory chaperone or anti-aggregant with activity against amyloidogenic clients including amyloid-beta and alpha-synuclein.
Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing.
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ProSAAS is a 260-aa neuroendocrine precursor cloned from human, mouse, and rat. mRNA is expressed primarily in brain and other neuroendocrine tissues (pituitary, adrenal, pancreas) and is broadly distributed among neurons.
"ProSAAS mRNA is expressed primarily in brain and other neuroendocrine tissues (pituitary, adrenal, pancreas); within brain, the mRNA is broadly distributed among neurons."
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ProSAAS is secreted via the regulated pathway from AtT-20 cells and is cleaved at paired-basic sites into smaller peptides.
"When expressed in AtT-20 cells, proSAAS is secreted via the regulated pathway and is also processed at paired-basic cleavage sites into smaller peptides."
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Purified ProSAAS inhibits PCSK1/PC1 activity (IC50 590 nM) but not PCSK2/PC2.
"Purified proSAAS inhibits prohormone convertase 1 activity with an IC(50) of 590 n m but does not inhibit prohormone convertase 2."
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ProSAAS overexpression substantially reduces processing of endogenous proopiomelanocortin in AtT-20 cells.
"Overexpression of proSAAS in the AtT-20 cells substantially reduces the rate of processing of the endogenous prohormone proopiomelanocortin."
Inhibitory specificity and potency of proSAAS-derived peptides toward proprotein convertase 1.
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Alanine scanning of the LLRVKR hexapeptide (residues 239-244) within the ProSAAS C-terminal inhibitory domain shows that single substitutions at K243 or R244 abolish inhibition of PCSK1, while substitutions at the flanking residues (V235, L236, G237, L240, R241, V242, L245, E246) reduce inhibition.
"The amino acids P1 Arg, P2 Lys, and P4 Arg are all critical for inhibition."
An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease.
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An N-terminal ProSAAS fragment accumulates with cytoplasmic tau inclusions in Pick's disease brain.
"the protein is an N-terminal fragment of proSAAS (a human granin-like neuroendocrine peptide precursor). Our results suggest that sequestration of the N-terminal fragment of proSAAS in intracellular PBs may cause a functional disturbance of neurons in Pick's disease."
A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam.
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ProSAAS N-terminal fragment immunoreactivity is associated with tau inclusions in Alzheimer's disease and the Guam parkinsonism-dementia complex.
"The antibody against N-proSAAS immunostained neurofibrillary tangles and neuritic plaques in both diseases, whereas the antibody against the C-terminal sequence of proSAAS did not."
A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease.
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ProSAAS exhibits anti-aggregant chaperone activity, preventing fibrillation of amyloid-beta (Aβ1-42) in vitro at substoichiometric ratios. Residues 97-180 of ProSAAS are sufficient.
"In vitro, proSAAS efficiently prevented the fibrillation of Aβ(1-42) at molar ratios of 1 : 10, and this anti-aggregation effect was dose dependent. Structure-function studies showed that residues 97-180 were sufficient for the anti-aggregation function against Aβ."
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ProSAAS co-immunoprecipitates with Aβ from APdE9 mouse brain and co-localizes with amyloid plaques in mouse and human AD brain.
"In the brains of 12-month-old APdE9 mice, and in the cortex of a human AD-affected brain, proSAAS immunoreactivity was highly colocalized with amyloid pathology. Immunoreactive proSAAS co-immunoprecipitated with Aβ immunoreactivity in lysates from APdE9 mouse brains."
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Recombinant ProSAAS in the medium and lentiviral ProSAAS overexpression block the neurocytotoxic effect of Aβ1-42 on Neuro2a cells.
"inclusion of recombinant proSAAS in the medium of Neuro2a cells, as well as lentiviral-mediated proSAAS over-expression, blocked the neurocytotoxic effect of Aβ(1-42) in Neuro2a cells."
The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity.
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Recombinant ProSAAS potently inhibits alpha-synuclein fibrillation in vitro; residues 158-180 are critical for the activity.
"Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158-180, containing a largely conserved element, are critical to this bioactivity."
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ProSAAS-encoding lentivirus blocks alpha-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons; recombinant ProSAAS blocks alpha-synuclein-induced cytotoxicity in SH-SY5Y cells.
"proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells."
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ProSAAS is associated with aggregated alpha-synuclein deposits in the substantia nigra of Parkinson's disease patients.
"proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson's disease."
The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.
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AAV/lentiviral ProSAAS overexpression rescues nigrostriatal dopaminergic neurons from AAV-alpha-synuclein toxicity in rats and reduces motor asymmetry.
"Coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This was accompanied by significant amelioration of the human aSyn-induced loss of both nigral TH-positive cells and striatal TH-positive terminals"
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ProSAAS overexpression blocks transsynaptic spread of alpha-synuclein from the vagus into the brain in mice.
"the number of human aSyn-positive neurites in the pons and caudal midbrain was considerably reduced in mice coinjected with proSAAS-, but not GFP-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission."
Sequestration of TDP-43(216-414) Aggregates by Cytoplasmic Expression of the proSAAS Chaperone.
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Forced cytoplasmic expression of ProSAAS (signal peptide removed) results in the formation of dense, membraneless 2 μm spheres that selectively encapsulate TDP-43 C-terminal aggregates and protect against TDP-43 toxicity in yeast. Authors describe ProSAAS as a "functional holdase". Caveat: ProSAAS is not normally cytoplasmic.
"We conclude that proSAAS can act as a functional holdase for TDP-43 via this phase-separation property"
Upstream curator request: term suitable to describe PCSK1N (ProSAAS) chaperone activity