id: Q9UHG2
gene_symbol: PCSK1N
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PCSK1N encodes ProSAAS (also called Proprotein convertase 1 inhibitor, pro-SAAS), a small
  neuroendocrine secretory precursor that is processed at paired basic sites in the regulated
  secretory pathway into multiple bioactive peptides. ProSAAS is expressed in neurons throughout the
  brain and in pituitary, adrenal, and pancreas, and is stored in dense-core secretory granules of the
  trans-Golgi network before regulated exocytosis. Its C-terminal Big PEN-LEN domain is an endogenous
  inhibitor of proprotein convertase 1/3, while full-length ProSAAS and an N-terminal fragment act as
  extracellular anti-aggregant chaperones that bind and prevent fibrillation of amyloidogenic clients
  including amyloid-beta, alpha-synuclein, and TDP-43. ProSAAS does not refold proteins or
  disaggregate preformed fibrils. In vivo, ProSAAS overexpression rescues dopaminergic neurons from
  alpha-synuclein toxicity and blocks transsynaptic alpha-synuclein spread in rodent Parkinson disease
  models. Processed PEN and Big LEN peptides function as endogenous neuropeptide ligands for GPR83 and
  GPR171, respectively.
existing_annotations:
- term:
    id: GO:0004866
    label: endopeptidase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation supported by clear experimental evidence that the C-terminal
      Big PEN-LEN region of ProSAAS inhibits PCSK1/PC1/3 (PMID:10632593,
      PMID:11435430). However, PCSK1 is a subtilisin-family serine endopeptidase,
      so the more specific child term GO:0004867 serine-type endopeptidase
      inhibitor activity (already on the GOA record as IEA) is preferable.
    action: KEEP_AS_NON_CORE
    reason: >-
      Generic parent of the more informative GO:0004867 already present. Retain
      to preserve the IBA phylogenetic annotation but treat as non-core in the
      synthesis since GO:0004867 captures the same activity at a more specific
      level.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Purified proSAAS inhibits prohormone convertase 1 activity with an
        IC(50) of 590 n m but does not inhibit prohormone convertase 2.
- term:
    id: GO:0004866
    label: endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA from InterPro (IPR010832 ProSAAS) recapitulating the IBA above.
      Same considerations apply: parent of the more specific GO:0004867.
    action: KEEP_AS_NON_CORE
    reason: >-
      InterPro2GO mapping is correct but redundant with the more specific
      GO:0004867 already present. Retained but not core.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Purified proSAAS inhibits prohormone convertase 1 activity with an
        IC(50) of 590 n m but does not inhibit prohormone convertase 2.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA combined-method annotation. ProSAAS is a regulated-secretory pathway
      protein that is released into the extracellular space. The annotation is
      correct but the more specific GO:0005615 extracellular space (used in the
      UniProt DR records) would be slightly more informative. Retained as
      accurate.
    action: ACCEPT
    reason: >-
      ProSAAS is genuinely secreted via the regulated pathway (PMID:10632593;
      UniProt SUBCELLULAR LOCATION). The IEA annotation is well supported.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        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.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA from UniProt SubCellular Location vocabulary (SL-0132). ProSAAS is
      processed by paired-basic cleavage in the Golgi (PMID:12914799). The
      child term GO:0005802 trans-Golgi network is more specific and is also
      annotated. Both can be retained.
    action: ACCEPT
    reason: >-
      Golgi localization is consistent with the regulated-secretory-pathway
      biology and with the documented proteolytic processing of ProSAAS in this
      compartment. Parent of the more specific trans-Golgi network annotation.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        proSAAS is secreted via the regulated pathway and is also processed at
        paired-basic cleavage sites into smaller peptides.
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA from Ensembl Compara orthology to mouse Q9QXV0. The C-terminal
      Big PEN-LEN region of ProSAAS is a specific inhibitor of PCSK1/PC1/3, a
      subtilisin-family serine endopeptidase (MEROPS S8). Alanine scanning of
      the LLRVKR hexapeptide (residues 239-244) shows that single substitutions
      at K243 or R244 abolish inhibition (PMID:11435430). The 2000 paper measured
      an IC50 of 590 nM for purified ProSAAS against PCSK1 and showed no
      inhibition of PCSK2 (PMID:10632593). This is the most informative and
      well-supported MF annotation on the record and represents one of the two
      core molecular functions.
    action: ACCEPT
    reason: >-
      Strongly supported by direct biochemical evidence (PMID:10632593,
      PMID:11435430) and by orthology. Most specific available MF term for the
      convertase-inhibitory activity. Promote to a core function.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Purified proSAAS inhibits prohormone convertase 1 activity with an
        IC(50) of 590 n m but does not inhibit prohormone convertase 2.
    - reference_id: PMID:11435430
      supporting_text: >-
        the decapeptide proSAAS-(235-244)( 235)VLGALLRVKR(244) is the most
        potent reversible competitive PC1-inhibitor (K(i) approximately 9 nm).
    - reference_id: file:human/PCSK1N/PCSK1N-deep-research-falcon.md
      supporting_text: "The report summarizes proSAAS as an endogenous PC1/3 inhibitor that modulates prohormone-processing protease activity in the regulated secretory pathway."
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA from Ensembl Compara orthology to mouse. UniProt curation places
      ProSAAS in the Golgi apparatus, trans-Golgi network. ProSAAS is processed
      by paired-basic cleavage at this location. Well-supported localization
      annotation.
    action: ACCEPT
    reason: >-
      ProSAAS is processed in the Golgi/TGN of the regulated secretory pathway
      (UniProt SUBCELLULAR LOCATION). Specific and informative.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        proSAAS is secreted via the regulated pathway and is also processed at
        paired-basic cleavage sites into smaller peptides.
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA from Ensembl Compara orthology to mouse. ProSAAS is stored in
      dense-core secretory granules of neuroendocrine cells (PMID:10632593,
      PMID:24102330) consistent with its regulated-secretory-pathway routing.
      Well-supported localization.
    action: ACCEPT
    reason: >-
      ProSAAS storage in regulated secretory granules is documented in the
      original characterization paper (PMID:10632593) and recapitulated by
      multiple subsequent studies.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        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.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from manual transfer of the experimentally-verified mouse annotation
      (UniProtKB:Q9QXV0). Equivalent to the IEA above. Retain as supporting.
    action: ACCEPT
    reason: >-
      Same as the IEA annotation: ProSAAS is secreted via the regulated pathway,
      well documented in PMID:10632593.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        When expressed in AtT-20 cells, proSAAS is secreted via the regulated
        pathway.
- term:
    id: GO:0004866
    label: endopeptidase inhibitor activity
  evidence_type: TAS
  original_reference_id: PMID:10632593
  review:
    summary: >-
      TAS from the original ProSAAS characterization paper. Same considerations
      as the IBA/IEA above: GO:0004867 (serine-type endopeptidase inhibitor
      activity) is the more specific and informative child term given that PCSK1
      is a serine endopeptidase, and that more specific term is already present
      on the GOA record.
    action: KEEP_AS_NON_CORE
    reason: >-
      Generic parent term. The more specific GO:0004867 child is already
      annotated and serves as the core MF; this entry is retained but
      considered non-core to keep the trio of GO:0004866 annotations
      consistent in their treatment.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Purified proSAAS inhibits prohormone convertase 1 activity with an
        IC(50) of 590 n m but does not inhibit prohormone convertase 2.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: TAS
  original_reference_id: PMID:10632593
  review:
    summary: >-
      TAS from the 2000 ProSAAS paper (PMID:10632593). The cited paper does NOT
      directly demonstrate receptor binding; it focuses on PCSK1 inhibition and
      tissue distribution. The annotation is presumably intended to capture the
      activity of the processed peptides Big LEN (GPR171 ligand, PMID:21795693
      Wardman et al., not cited here) and PEN (GPR83 ligand, PMID:23690615
      Gomes et al., not cited here). Even granting the underlying biology, the
      term is non-specific and the cited reference does not support it. The
      activity is also peptide-product-specific (Big LEN, PEN), not a property
      of full-length ProSAAS.
    action: REMOVE
    reason: >-
      The peptide-receptor binding biology may be real for processed peptide
      products such as Big LEN and PEN, but the cited PMID does not demonstrate
      receptor binding and instead supports PCSK1 inhibition and regulated
      secretion of the precursor. Remove this unsupported precursor-level TAS
      annotation; processed peptide ligands should be re-annotated separately
      using direct GPR171/GPR83 evidence if appropriate.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Taken together, proSAAS may represent an endogenous inhibitor of
        prohormone convertase 1.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: PMID:10632593
  review:
    summary: >-
      TAS from the original ProSAAS characterization paper, which documents
      regulated secretion of ProSAAS from AtT-20 cells. Well-supported
      localization.
    action: ACCEPT
    reason: >-
      Directly demonstrated in the cited paper.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        When expressed in AtT-20 cells, proSAAS is secreted via the regulated
        pathway.
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:24102330
  review:
    summary: >-
      Proposed NEW annotation. Direct biochemical evidence shows that ProSAAS
      binds amyloid-beta and prevents its fibrillation in vitro at
      substoichiometric ratios; ProSAAS co-immunoprecipitates with Aβ in APdE9
      mouse brain. Additional evidence in PMID:27457957 (alpha-synuclein) and
      PMID:35527562 (alpha-synuclein in vivo). This MF (or its more specific
      child GO:0001540 amyloid-beta binding) is the appropriate primary term
      for the "anti-aggregant chaperone" activity highlighted in upstream
      go-annotation issue #6407, since ProSAAS does not refold clients (so
      GO:0044183 is inappropriate) and does not perform a documented
      carrier/handoff (so GO:0140309 unfolded protein holdase activity is at
      best a partial fit). The CLU/clusterin curation in this repository uses
      the same MF for an analogous extracellular anti-aggregant chaperone.
    action: NEW
    reason: >-
      Captures the secreted anti-aggregant chaperone activity of ProSAAS
      established in PMID:24102330, PMID:27457957, PMID:35527562 (and
      PMID:35549000 for cytoplasmic capacity).
    supported_by:
    - reference_id: PMID:24102330
      supporting_text: >-
        We here describe a novel anti-aggregant chaperone function for the
        neuroendocrine protein proSAAS, an abundant secretory polypeptide that
        is widely expressed within neural and endocrine tissues
    - reference_id: PMID:27457957
      supporting_text: >-
        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.
    - reference_id: file:human/PCSK1N/PCSK1N-deep-research-falcon.md
      supporting_text: "The report summarizes proSAAS as a secretory chaperone/anti-aggregant that can limit fibrillation or aggregation of amyloid-beta, alpha-synuclein, and islet amyloid polypeptide."
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IPI
  original_reference_id: PMID:24102330
  review:
    summary: >-
      Proposed NEW annotation. PMID:24102330 provides amyloid-beta-specific
      physical-interaction evidence: ProSAAS co-immunoprecipitates with Aβ from
      APdE9 mouse brain lysates and recombinant ProSAAS prevents Aβ(1-42)
      fibrillation in vitro. This child term captures the amyloid-beta component
      of the broader misfolded-protein-binding activity.
    action: NEW
    reason: >-
      The notes explicitly identify amyloid-beta binding as a supported,
      more-specific MF term for the Aβ co-IP and anti-fibrillation evidence.
      Add it alongside GO:0051787 rather than relying only on the broader
      misfolded protein binding parent.
    supported_by:
    - reference_id: PMID:24102330
      supporting_text: >-
        Immunoreactive proSAAS co-immunoprecipitated with Aβ immunoreactivity in
        lysates from APdE9 mouse brains.
    - reference_id: PMID:24102330
      supporting_text: >-
        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.
- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: IDA
  original_reference_id: PMID:24102330
  review:
    summary: >-
      Proposed NEW BP annotation. ProSAAS prevents amyloid-beta fibrillation
      in vitro at substoichiometric ratios (PMID:24102330) and inhibits
      alpha-synuclein fibrillation in vitro (PMID:27457957), with in vivo
      neuroprotective consequences in rodent models of Parkinson's disease
      (PMID:35527562). GO:1902430 (negative regulation of amyloid-beta
      formation) is NOT recommended because that term refers to the
      proteolytic generation of Aβ from APP, not to its aggregation.
    action: NEW
    reason: >-
      Best-fitting BP term for the anti-fibrillation activity directly
      demonstrated in vitro and in vivo for two amyloidogenic clients.
    supported_by:
    - reference_id: PMID:24102330
      supporting_text: >-
        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.
    - reference_id: PMID:27457957
      supporting_text: >-
        Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in
        an in vitro assay
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:24102330
  review:
    summary: >-
      Proposed NEW BP annotation, parent of holdase-like client stabilization.
      The CLU/clusterin curation uses this BP alongside GO:1905907 to capture
      the extracellular maintenance of misfolded clients in soluble
      non-aggregating states. The same logic applies to ProSAAS.
    action: NEW
    reason: >-
      Captures the chaperone-mediated stabilization of misfolded amyloidogenic
      clients in soluble (non-aggregating) form.
    supported_by:
    - reference_id: PMID:24102330
      supporting_text: >-
        We here describe a novel anti-aggregant chaperone function for the
        neuroendocrine protein proSAAS
    - reference_id: PMID:27457957
      supporting_text: >-
        the small secretory chaperone known as proSAAS (named after four
        residues in the amino terminal region) has many attractive properties.
- term:
    id: GO:0010955
    label: negative regulation of protein processing
  evidence_type: IDA
  original_reference_id: PMID:10632593
  review:
    summary: >-
      Proposed NEW BP annotation. ProSAAS overexpression slows processing of
      proopiomelanocortin (a PCSK1 substrate) in AtT-20 cells. The convertase-
      inhibitory activity of ProSAAS exerts its biological effect by negatively
      regulating prohormone processing; this is the appropriate BP for the
      core MF GO:0004867 serine-type endopeptidase inhibitor activity.
    action: NEW
    reason: >-
      The molecular function (PCSK1 inhibition) acts upon prohormone processing
      reactions; this BP captures the consequence in the regulated secretory
      pathway.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Overexpression of proSAAS in the AtT-20 cells substantially reduces the
        rate of processing of the endogenous prohormone proopiomelanocortin.
- term:
    id: GO:0060570
    label: negative regulation of peptide hormone processing
  evidence_type: IDA
  original_reference_id: PMID:10632593
  review:
    summary: >-
      Proposed NEW BP annotation. The substrate of ProSAAS-inhibited PCSK1 is
      proopiomelanocortin (a peptide-hormone precursor) and other prohormones,
      making this a more specific and biologically informative BP than
      GO:0010955.
    action: NEW
    reason: >-
      Specific child of GO:0010955 capturing the prohormone-processing context
      that is the actual physiological role.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        Overexpression of proSAAS in the AtT-20 cells substantially reduces the
        rate of processing of the endogenous prohormone proopiomelanocortin.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:10632593
  review:
    summary: >-
      Proposed NEW CC annotation, more specific child of GO:0005576
      extracellular region. ProSAAS is released by regulated exocytosis into
      the extracellular space, where its anti-aggregant chaperone activity is
      thought to act on extracellular amyloidogenic clients (e.g. extracellular
      Aβ aggregates in PMID:24102330; extracellular alpha-synuclein in
      PMID:35527562 transsynaptic-spread experiments).
    action: NEW
    reason: >-
      Specific child of GO:0005576 reflecting the exocytotic release into the
      extracellular space; this is the site of anti-aggregant chaperone action.
    supported_by:
    - reference_id: PMID:10632593
      supporting_text: >-
        proSAAS is secreted via the regulated pathway
core_functions:
- description: >-
    The C-terminal Big PEN-LEN region of ProSAAS (residues 221-260, containing
    the LLRVKR hexapeptide motif at 239-244) is a potent and specific endogenous
    inhibitor of the subtilisin-family serine endopeptidase PCSK1/PC1/3. ProSAAS
    binds PCSK1 and slows convertase-mediated processing of prohormones such as
    proopiomelanocortin and proenkephalin in the regulated secretory pathway,
    thereby modulating the timing and extent of peptide hormone maturation.
    Inhibition is selective for PCSK1 over the related convertase PCSK2.
    Subsequent processing of ProSAAS to the smaller peptides eliminates the
    inhibition, providing a built-in temporal switch.
  molecular_function:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  directly_involved_in:
  - id: GO:0010955
    label: negative regulation of protein processing
  - id: GO:0060570
    label: negative regulation of peptide hormone processing
  locations:
  - id: GO:0005802
    label: trans-Golgi network
  - id: GO:0030141
    label: secretory granule
  - id: GO:0005576
    label: extracellular region
  substrates:
  - id: UniProtKB:P29120
    label: PCSK1 (PC1/3)
  supported_by:
  - reference_id: PMID:10632593
    supporting_text: >-
      Purified proSAAS inhibits prohormone convertase 1 activity with an
      IC(50) of 590 n m but does not inhibit prohormone convertase 2.
  - reference_id: PMID:10632593
    supporting_text: >-
      Overexpression of proSAAS in the AtT-20 cells substantially reduces the
      rate of processing of the endogenous prohormone proopiomelanocortin.
  - reference_id: PMID:11435430
    supporting_text: >-
      the decapeptide proSAAS-(235-244)( 235)VLGALLRVKR(244) is the most potent
      reversible competitive PC1-inhibitor (K(i) approximately 9 nm).
  - reference_id: file:human/PCSK1N/PCSK1N-deep-research-falcon.md
    supporting_text: "Canonical function: PCSK1N/proSAAS is a potent inhibitor of PC1/3 in the regulated secretory pathway, modulating prohormone processing in endocrine cells and islets."
- description: >-
    Full-length ProSAAS (and the 21 kDa N-terminal fragment, residues ~1-180)
    is an extracellular anti-aggregant chaperone that binds amyloidogenic
    clients and prevents their fibrillation. Direct biochemical evidence
    includes substoichiometric inhibition of amyloid-beta (Aβ1-42)
    fibrillation in thioflavin-T assays (residues 97-180 sufficient,
    PMID:24102330) and of alpha-synuclein fibrillation (residues 158-180
    critical, PMID:27457957). ProSAAS co-immunoprecipitates with Aβ from
    APdE9 mouse brain and co-localizes with amyloid pathology and with
    aggregated alpha-synuclein deposits in Parkinson's-disease substantia
    nigra. Anti-aggregant activity translates to in vivo neuroprotection:
    AAV/lentiviral ProSAAS overexpression rescues dopaminergic neurons from
    alpha-synuclein toxicity and blocks transsynaptic spread of
    alpha-synuclein in rodent Parkinson's-disease models (PMID:35527562).
    ProSAAS does NOT refold unfolded clients and does NOT disaggregate
    preformed fibrils, so it is not a foldase or a disaggregase. The
    Lindberg group has used the term "holdase" to describe its sequestration
    of TDP-43 aggregates in cytoplasmic membraneless spheres (PMID:35549000),
    but the GO definition of unfolded protein holdase activity (GO:0140309)
    emphasizes a carrier/delivery function that is not formally established
    for ProSAAS in vivo. The most defensible representation is therefore
    misfolded protein binding (with amyloid-beta binding as a more specific
    child) coupled to the BP "negative regulation of amyloid fibril formation".
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  directly_involved_in:
  - id: GO:1905907
    label: negative regulation of amyloid fibril formation
  - id: GO:0050821
    label: protein stabilization
  locations:
  - id: GO:0005576
    label: extracellular region
  - id: GO:0030141
    label: secretory granule
  supported_by:
  - reference_id: PMID:24102330
    supporting_text: >-
      We here describe a novel anti-aggregant chaperone function for the
      neuroendocrine protein proSAAS, an abundant secretory polypeptide that
      is widely expressed within neural and endocrine tissues
  - reference_id: PMID:24102330
    supporting_text: >-
      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.
  - reference_id: PMID:24102330
    supporting_text: >-
      Immunoreactive proSAAS co-immunoprecipitated with Aβ immunoreactivity in
      lysates from APdE9 mouse brains.
  - reference_id: PMID:27457957
    supporting_text: >-
      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.
  - reference_id: PMID:35527562
    supporting_text: >-
      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
  - reference_id: PMID:35527562
    supporting_text: >-
      proSAAS, a small neuronal chaperone, blocks aSyn-induced dopaminergic
      cytotoxicity in primary nigral cultures.
  - reference_id: PMID:35549000
    supporting_text: >-
      We previously demonstrated that proSAAS, a small secreted neuronal
      protein, exhibits potent chaperone activity against protein aggregation
      in vitro and blocks the cytotoxic effects of amyloid and synuclein
      oligomers in cell culture systems.
  - reference_id: file:human/PCSK1N/PCSK1N-deep-research-falcon.md
    supporting_text: "Emerging function: proSAAS also acts as a secretory chaperone/anti-aggregant, blocking fibrillation or aggregation of amyloid-beta, alpha-synuclein, and islet amyloid polypeptide in vitro and protecting cells from toxic oligomers."
proposed_new_terms: []
suggested_questions:
- question: >-
    Should an extracellular anti-aggregant chaperone that prevents fibrillation
    but does not refold clients and does not perform a documented carrier/handoff
    be annotated to GO:0051787 misfolded protein binding (plus BP GO:1905907
    negative regulation of amyloid fibril formation), or to GO:0140309 unfolded
    protein holdase activity? The CLU/clusterin curation in this repository uses
    the GO:0051787 + GO:1905907 + GO:0050821 combination for an analogous
    activity; the SCG5/7B2 review takes a similar approach. Is this the agreed
    convention for "anti-aggregant" chaperones, or is a new MF term warranted?
  experts:
  - I. Lindberg
- question: >-
    The TDP-43-encapsulating sphere phenotype reported in PMID:35549000 was
    obtained by deliberately removing ProSAAS's signal peptide to force
    cytoplasmic expression. Should this evidence be used to support a normal
    cellular MF (holdase activity) or restricted to "demonstrates capacity for
    prion-like client binding" with no associated cellular component
    annotation? ProSAAS does not normally reach the cytoplasm.
  experts:
  - I. Lindberg
  - J. Shorter
- question: >-
    Are PEN (GPR83 ligand) and Big LEN (GPR171 ligand) better captured by
    annotating the cleavage products as separate functional isoforms with
    their own MF (peptide-receptor ligand activity) and BP (G protein-coupled
    receptor signaling pathway) annotations, rather than by the current
    GO:0005102 signaling receptor binding annotation on the precursor?
  experts:
  - L. Devi
  - L. Fricker
suggested_experiments:
- hypothesis: >-
    Endogenous (rather than transgenic) ProSAAS limits alpha-synuclein
    fibrillation and transsynaptic spread in vivo.
  description: >-
    PCSK1N knockout (or neuron-specific conditional KO) crossed with
    AAV-alpha-synuclein PD models, with quantification of nigrostriatal TH
    loss, motor asymmetry, and rostral spread of alpha-synuclein after vagal
    AAV-aSyn injection. Compares the gain-of-function PMID:35527562 result
    against the loss-of-function condition.
  experiment_type: in vivo mouse genetics + viral aggregation models
- hypothesis: >-
    Recombinant ProSAAS binds amyloidogenic clients with stoichiometry and
    kinetics consistent with classical sub-stoichiometric "holdase" chaperones
    (e.g. small heat shock proteins, clusterin) and the binding is to
    monomers/early oligomers rather than mature fibrils.
  description: >-
    Surface plasmon resonance and microscale thermophoresis with purified
    ProSAAS and Aβ(1-42), alpha-synuclein, IAPP at defined assembly stages
    (monomer, oligomer, protofibril, mature fibril). Combine with AFM/EM to
    correlate binding modes with fibrillation outcome. Establishes whether the
    activity is on-pathway sequestration (holdase-like) versus passive
    co-aggregation.
  experiment_type: biophysical binding + fibrillation kinetics
- hypothesis: >-
    The N-terminal SAAS deposits in tau inclusions of Pick's disease and AD
    are a consequence of proteostatic dysregulation rather than ProSAAS
    actively driving tau pathology.
  description: >-
    Immuno-EM and antibody mapping of N-terminal SAAS fragments in human AD
    and Pick's disease brain combined with PCSK1N gain- and loss-of-function
    in iPSC-derived tauopathy organoids; assess whether ProSAAS modulates tau
    fibrillation in vitro.
  experiment_type: human neuropathology + iPSC functional study
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/PCSK1N/PCSK1N-deep-research-falcon.md
  title: Falcon deep research report for human PCSK1N
  findings:
  - statement: PCSK1N encodes proSAAS, a regulated-secretory-pathway precursor and endogenous PC1/3 inhibitor that modulates prohormone processing in secretory granules.
  - statement: The report also supports proSAAS as a secretory chaperone or anti-aggregant with activity against amyloidogenic clients including amyloid-beta and alpha-synuclein.
- id: PMID:10632593
  title: Identification and characterization of proSAAS, a granin-like neuroendocrine
    peptide precursor that inhibits prohormone processing.
  findings:
  - statement: >-
      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.
    supporting_text: >-
      ProSAAS mRNA is expressed primarily in brain and other neuroendocrine
      tissues (pituitary, adrenal, pancreas); within brain, the mRNA is broadly
      distributed among neurons.
    reference_section_type: ABSTRACT
  - statement: >-
      ProSAAS is secreted via the regulated pathway from AtT-20 cells and is
      cleaved at paired-basic sites into smaller peptides.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      Purified ProSAAS inhibits PCSK1/PC1 activity (IC50 590 nM) but not PCSK2/PC2.
    supporting_text: >-
      Purified proSAAS inhibits prohormone convertase 1 activity with an IC(50)
      of 590 n m but does not inhibit prohormone convertase 2.
    reference_section_type: ABSTRACT
  - statement: >-
      ProSAAS overexpression substantially reduces processing of endogenous
      proopiomelanocortin in AtT-20 cells.
    supporting_text: >-
      Overexpression of proSAAS in the AtT-20 cells substantially reduces the
      rate of processing of the endogenous prohormone proopiomelanocortin.
    reference_section_type: ABSTRACT
- id: PMID:11435430
  title: Inhibitory specificity and potency of proSAAS-derived peptides toward
    proprotein convertase 1.
  findings:
  - statement: >-
      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.
    supporting_text: >-
      The amino acids P1 Arg, P2 Lys, and P4 Arg are all critical for
      inhibition.
    reference_section_type: ABSTRACT
- id: PMID:12914799
  title: An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide
    precursor) is associated with tau inclusions in Pick's disease.
  findings:
  - statement: >-
      An N-terminal ProSAAS fragment accumulates with cytoplasmic tau inclusions
      in Pick's disease brain.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
- id: PMID:14746899
  title: A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity
    in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam.
  findings:
  - statement: >-
      ProSAAS N-terminal fragment immunoreactivity is associated with tau
      inclusions in Alzheimer's disease and the Guam parkinsonism-dementia
      complex.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
- id: PMID:24102330
  title: A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's
    disease.
  findings:
  - statement: >-
      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.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      ProSAAS co-immunoprecipitates with Aβ from APdE9 mouse brain and
      co-localizes with amyloid plaques in mouse and human AD brain.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      Recombinant ProSAAS in the medium and lentiviral ProSAAS overexpression
      block the neurocytotoxic effect of Aβ1-42 on Neuro2a cells.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
- id: PMID:27457957
  title: The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity.
  full_text_unavailable: true
  findings:
  - statement: >-
      Recombinant ProSAAS potently inhibits alpha-synuclein fibrillation in
      vitro; residues 158-180 are critical for the activity.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      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.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      ProSAAS is associated with aggregated alpha-synuclein deposits in the
      substantia nigra of Parkinson's disease patients.
    supporting_text: >-
      proSAAS, widely expressed in neurons throughout the brain, is associated
      with aggregated synuclein deposits in the substantia nigra of patients
      with Parkinson's disease.
    reference_section_type: ABSTRACT
- id: PMID:35527562
  title: The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic
    α-Synuclein Spread in Rodent Models of Parkinson's Disease.
  findings:
  - statement: >-
      AAV/lentiviral ProSAAS overexpression rescues nigrostriatal dopaminergic
      neurons from AAV-alpha-synuclein toxicity in rats and reduces motor
      asymmetry.
    supporting_text: >-
      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
    reference_section_type: ABSTRACT
  - statement: >-
      ProSAAS overexpression blocks transsynaptic spread of alpha-synuclein
      from the vagus into the brain in mice.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
- id: PMID:35549000
  title: Sequestration of TDP-43(216-414) Aggregates by Cytoplasmic Expression of
    the proSAAS Chaperone.
  findings:
  - statement: >-
      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.
    supporting_text: >-
      We conclude that proSAAS can act as a functional holdase for TDP-43 via
      this phase-separation property
    reference_section_type: ABSTRACT
- id: 'geneontology/go-annotation#6407'
  title: 'Upstream curator request: term suitable to describe PCSK1N (ProSAAS) chaperone activity'
  findings: []