CRISP3 encodes a cysteine-rich secretory protein that is primarily localized to specific and tertiary granules in neutrophils and eosinophils. It is secreted into extracellular fluids including plasma, saliva, seminal plasma, and exocrine secretions, with particularly strong expression in the cauda epididymis and ampulla/vas deferens of the male reproductive tract. CRISP3 plays a role in innate immune response and is also expressed in reproductive tissues. As a member of the CAP/CRISP superfamily, the protein functions as a ligand-binding/interaction protein (rather than as a catalytic enzyme), with an N-terminal CAP domain and a C-terminal cysteine-rich (CRISP) domain implicated in ion channel regulation. Documented binding partners include beta-microseminoprotein (MSMB/PSP94) in seminal plasma, alpha-1-B-glycoprotein (A1BG) at nanomolar affinity, and the plasma membrane Ca2+ exporter PMCA4b (ATP2B4) via the CAP domain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for extracellular space is strongly supported by multiple experimental studies showing CRISP3 in plasma, saliva, seminal plasma, sweat, and as a secreted protein from neutrophil granules. Reason: Multiple experimental studies confirm CRISP3 is secreted into extracellular fluids. PMID:12009203 detected CRISP3 in human plasma (6.3 ΞΌg/ml), saliva (21.8 ΞΌg/ml), seminal plasma (11.2 ΞΌg/ml), and sweat (0.15 ΞΌg/ml). PMID:8601434 characterized it as a secretory protein. PMID:12223513 demonstrated it is released from neutrophil granules. The IBA annotation at the extracellular space level is appropriate and specific. Supporting Evidence: PMID:12009203 We further demonstrate the presence of CRISP-3 protein in human plasma (6.3 microg/ml), saliva (21.8 microg/ml), seminal plasma (11.2 microg/ml), and sweat (0.15 microg/ml) PMID:12223513 CRISP-3 was found to be a matrix protein, which is stored in granules as glycosylated and as unglycosylated protein file:human/CRISP3/CRISP3-deep-research-perplexity-lite.md provider: perplexity file:human/CRISP3/CRISP3-deep-research-falcon.md CRISP3/SGP28 is localized to **neutrophil granules** (including specific and gelatinase granules) and is measurable in circulation and secretions, supporting a role in extracellular or luminal environments after degranulation/secretion. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for extracellular region is correct but less specific than the more precise GO:0005615 (extracellular space) annotation. This broader term is acceptable as an IEA annotation. Reason: The protein is indeed located in the extracellular region. However, this term is less specific than GO:0005615 (extracellular space), which is supported by IBA and experimental evidence. Since this is an automated IEA annotation and the more specific term is already present, this broader annotation is acceptable but redundant with better annotations. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798745 | ACCEPT | Summary: TAS annotation from Reactome pathway R-HSA-6798745 (Exocytosis of tertiary granule lumen proteins) is correct, representing the destination of CRISP3 after exocytosis from tertiary granules. Reason: CRISP3 is released into the extracellular region upon exocytosis of tertiary granules. The Reactome pathway R-HSA-6798745 documents exocytosis of tertiary granule lumen proteins. PMID:12223513 demonstrates CRISP3 is found in tertiary (gelatinase) granules and is released upon neutrophil activation. Supporting Evidence: Reactome:R-HSA-6798745 Tertiary (gelatinase) granules are part of a continuum of peroxidase-negative granules formed in myelocytes, metamyelocytes, band cells and segmented neutrophils |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798749 | ACCEPT | Summary: TAS annotation from Reactome pathway R-HSA-6798749 (Exocytosis of specific granule lumen proteins) is correct, representing the destination of CRISP3 after exocytosis from specific granules. Reason: CRISP3 is released into the extracellular region upon exocytosis of specific granules. The Reactome pathway R-HSA-6798749 documents exocytosis of specific granule lumen proteins. PMID:8601434 and PMID:12223513 clearly demonstrate CRISP3 localization in specific granules of neutrophils. Supporting Evidence: PMID:8601434 Subcellular fractionation of human neutrophils indicated that the protein is localized in specific granules Reactome:R-HSA-6798749 Secondary (specific) granules are peroxidase-negative and rich in antimicrobial substances |
| GO:0035580 specific granule lumen | TAS Reactome:R-HSA-6798749 | ACCEPT | Summary: TAS annotation for specific granule lumen is strongly supported by direct experimental evidence showing CRISP3 as a matrix protein within specific granules of neutrophils. Reason: CRISP3 is definitively localized to the lumen of specific granules in neutrophils. PMID:8601434 identified it as a specific granule protein (SGP28). PMID:12223513 characterized it as a matrix protein localized in specific granules using subcellular fractionation and immunogold electron microscopy. This is a core localization for CRISP3. Supporting Evidence: PMID:8601434 Subcellular fractionation of human neutrophils indicated that the protein is localized in specific granules. The protein was named SGP28 (specific granule protein of 28 kDa) PMID:12223513 CRISP-3 was found to be localized in a subset of granules with overlapping characteristics of specific and gelatinase granules and mobilized accordingly |
| GO:1904724 tertiary granule lumen | TAS Reactome:R-HSA-6798745 | ACCEPT | Summary: TAS annotation for tertiary granule lumen is supported by evidence showing CRISP3 in a continuum of peroxidase-negative granules including tertiary (gelatinase) granules. Reason: PMID:12223513 demonstrates that CRISP3 is localized in a subset of granules with overlapping characteristics of specific and gelatinase (tertiary) granules, confirming it exists as part of a continuum of peroxidase-negative granules. The Reactome pathway R-HSA-6798745 accurately represents this aspect of CRISP3 localization. Supporting Evidence: PMID:12223513 CRISP-3 was found to be localized in a subset of granules with overlapping characteristics of specific and gelatinase granules and mobilized accordingly, thus confirming the hypothesis that peroxidase-negative granules exist as a continuum from specific to gelatinase granules |
| GO:0005615 extracellular space | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | ACCEPT | Summary: HDA annotation based on proteomics identification of CRISP3 in human colostrum, a secreted extracellular fluid. This supports the extracellular space localization. Reason: PMID:16502470 is a proteomics study that identified CRISP3 as one of 151 proteins in the aqueous phase of human colostrum. Colostrum is an extracellular secretion, confirming CRISP3 presence in extracellular space. This complements other evidence for secretion into various extracellular fluids. Supporting Evidence: PMID:16502470 We have investigated the low abundance proteins in the aqueous phase of human colostrum, after depletion of the major proteins secretory IgA, lactoferrin, alpha-lactalbumin and HSA by immunoabsorption, using 2-D LC and gel-based proteomic methods. One hundred and fifty-one proteins were identified |
| GO:0005576 extracellular region | IDA PMID:12009203 An ELISA for SGP28/CRISP-3, a cysteine-rich secretory protei... | ACCEPT | Summary: IDA annotation based on ELISA detection of CRISP3 in plasma, saliva, seminal plasma, and sweat. While correct, the more specific term GO:0005615 (extracellular space) would be more appropriate. Reason: PMID:12009203 used ELISA to directly detect CRISP3 protein in various extracellular secretions (plasma, saliva, seminal plasma, sweat), providing direct experimental evidence for extracellular region localization. Although GO:0005615 (extracellular space) is more specific and also supported by this study, the broader extracellular region term is technically correct. Supporting Evidence: PMID:12009203 We further demonstrate the presence of CRISP-3 protein in human plasma (6.3 microg/ml), saliva (21.8 microg/ml), seminal plasma (11.2 microg/ml), and sweat (0.15 microg/ml) |
| GO:0005576 extracellular region | IDA PMID:12223513 Identification of human cysteine-rich secretory protein 3 (C... | ACCEPT | Summary: IDA annotation based on immunogold electron microscopy and subcellular fractionation showing CRISP3 in neutrophil granules that are released extracellularly. Reason: PMID:12223513 used subcellular fractionation and double-labeling immunogold electron microscopy to directly demonstrate CRISP3 localization in granules and its release upon neutrophil activation. The study explicitly states CRISP3 is found in exocrine secretions, indicating extracellular region localization. This is experimentally sound IDA evidence. Supporting Evidence: PMID:12223513 The presence of CRISP-3 in peroxidase-negative granules of neutrophils, in granules of eosinophils, and in exocrine secretions indicates a role in the innate host defense |
| GO:0005576 extracellular region | IDA PMID:12433721 Cysteine-rich secretory protein-3: a potential biomarker for... | ACCEPT | Summary: IDA annotation based on transfection studies demonstrating CRISP3 is a secretory protein, confirming extracellular region localization. Reason: PMID:12433721 performed transient transfection studies and demonstrated that CRISP3 is a secretory protein, providing direct experimental evidence for extracellular localization. The study focused on CRISP3 as a prostate cancer biomarker and confirmed its secreted nature, which is consistent with its presence in extracellular fluids. Supporting Evidence: PMID:12433721 In transient transfection studies, CRISP-3 was found to be a secretory protein |
| GO:0005576 extracellular region | IDA PMID:8601434 SGP28, a novel matrix glycoprotein in specific granules of h... | ACCEPT | Summary: IDA annotation based on the original characterization of CRISP3 (SGP28) showing it is released from neutrophil specific granules into the extracellular space. Reason: PMID:8601434 is the original study that identified and characterized CRISP3 (then named SGP28). The study purified the protein from exocytosed material from human neutrophils, providing direct experimental evidence that the protein is secreted into the extracellular region. This is foundational IDA evidence for extracellular localization. Supporting Evidence: PMID:8601434 A novel 28 kDa glycoprotein was purified from exocytosed material from human neutrophils and its primary structure partially determined |
| GO:0006952 defense response | NAS PMID:12647793 Preferential expression of cystein-rich secretory protein-3 ... | MODIFY | Summary: NAS annotation for defense response is based on CRISP3 expression pattern in chronic pancreatitis and its classification as a defense-associated molecule. However, this is too broad - the more specific GO:0045087 (innate immune response) is better supported. Reason: PMID:12647793 identifies CRISP3 as a "defense-associated molecule" and shows upregulation in chronic pancreatitis, suggesting a defensive role. However, this is a very broad term. The evidence from neutrophil and eosinophil granule localization, presence in exocrine secretions, and similarity to pathogenesis-related proteins more specifically supports GO:0045087 (innate immune response), which is already annotated. The defense response annotation is not wrong but is overly general. Proposed replacements: innate immune response Supporting Evidence: PMID:12647793 Cysteine-rich secretory protein (CRISP-3) has been identified as a defense-associated molecule with predominant expression in the salivary gland, pancreas and prostate |
| GO:0031012 extracellular matrix | NAS PMID:12223513 Identification of human cysteine-rich secretory protein 3 (C... | REMOVE | Summary: NAS annotation for extracellular matrix is based on CRISP3 being called a "matrix protein" in granules, but this terminology refers to the granule matrix, not the extracellular matrix. This is a misinterpretation. Reason: PMID:12223513 describes CRISP3 as a "matrix protein" but this refers to the protein matrix within the granule lumen, not the extracellular matrix. The paper states "CRISP-3 was found to be a matrix protein, which is stored in granules" - this is about intragranular localization. There is no evidence that CRISP3 is a structural component of the extracellular matrix like collagens, laminins, or fibronectins. The protein is found in extracellular space/fluids, but not in the ECM proper. Supporting Evidence: PMID:12223513 CRISP-3 was found to be a matrix protein, which is stored in granules as glycosylated and as unglycosylated protein |
| GO:0042581 specific granule | IDA PMID:12223513 Identification of human cysteine-rich secretory protein 3 (C... | ACCEPT | Summary: IDA annotation for specific granule is strongly supported by subcellular fractionation and immunogold electron microscopy showing CRISP3 localization in specific granules of neutrophils. Reason: PMID:12223513 used multiple experimental approaches including subcellular fractionation on Percoll density gradients, release studies with secretagogues, and double-labeling immunogold electron microscopy to directly demonstrate CRISP3 localization in specific granules. This is high-quality IDA evidence. The specific granule localization is a core feature of CRISP3 biology. Supporting Evidence: PMID:12223513 To investigate the subcellular localization and mobilization of CRISP-3 in human neutrophils, we performed subcellular fractionation of resting and activated neutrophils on three-layer Percoll density gradients, release-studies of granule proteins in response to different secretagogues, and double-labeling immunogold electron microscopy |
| GO:0042581 specific granule | IDA PMID:8601434 SGP28, a novel matrix glycoprotein in specific granules of h... | ACCEPT | Summary: IDA annotation for specific granule based on the original characterization study that named the protein SGP28 (specific granule protein of 28 kDa) using subcellular fractionation. Reason: PMID:8601434 is the foundational study that originally characterized CRISP3 as SGP28 (specific granule protein of 28 kDa). The study used subcellular fractionation to demonstrate localization in specific granules of neutrophils. This is the original direct experimental evidence that established CRISP3 as a specific granule protein. Supporting Evidence: PMID:8601434 Subcellular fractionation of human neutrophils indicated that the protein is localized in specific granules. The protein was named SGP28 (specific granule protein of 28 kDa) |
| GO:0045087 innate immune response | NAS PMID:12223513 Identification of human cysteine-rich secretory protein 3 (C... | ACCEPT | Summary: NAS annotation for innate immune response is well-supported by CRISP3 localization in neutrophil and eosinophil granules, presence in exocrine secretions, and similarity to pathogenesis-related proteins. Reason: PMID:12223513 provides strong indirect evidence for CRISP3 involvement in innate immunity. The study demonstrates CRISP3 in peroxidase-negative granules of neutrophils, granules of eosinophils, and exocrine secretions - all components of innate host defense. The authors explicitly state this indicates a role in innate host defense. Additionally, PMID:12009203 notes similarity to pathogenesis-related proteins in plants, further supporting an innate immune function. Supporting Evidence: PMID:12223513 The presence of CRISP-3 in peroxidase-negative granules of neutrophils, in granules of eosinophils, and in exocrine secretions indicates a role in the innate host defense PMID:12009203 Similarities to pathogenesis-related proteins in plants and the expression in neutrophils and exocrine glands suggest that SGP28/CRISP-3 may play a role in innate host defense file:human/CRISP3/CRISP3-deep-research-falcon.md CRISP3's dual association with **neutrophil granules** and **male reproductive tract secretions** supports two plausible biology axes: (i) **innate immune degranulation/secreted protein biology** |
| GO:0032934 sterol binding | NAS | NEW | Summary: Added based on the CAP/CRISP family sterol-binding/export functional axis demonstrated for CRISP2 in El Atab et al. 2024 (PMID:39433128), where A1BG binds CRISP-family proteins (including CRISP3) at nanomolar affinity and inhibits sterol secretion/export. Direct sterol-binding activity for hCRISP3 has not been demonstrated; this is a family/paralog-level inference. Reason: The falcon deep research surfaces a CAP-family sterol-binding/export function that is plausible for CRISP3 by sequence/structure homology to CRISP2 and via the demonstrated nanomolar CRISP3-A1BG interaction. Annotated as NEW with NAS evidence rather than asserted as accepted, pending direct biochemistry on hCRISP3. Supporting Evidence: PMID:39433128 We demonstrate that coexpression of A1BG with CRISP2 or CRISP3 impedes the sterol export function of CRISP proteins in vivo without affecting their secretion. PMID:39433128 Coexpression of A1BG with CAP proteins abolished their sterol export function in yeast and their interaction inhibits sterol-binding in vitro. file:human/CRISP3/CRISP3-deep-research-falcon.md CRISP3 is an abundant seminal plasma protein that can bind **alpha-1-B glycoprotein (A1BG)** with **nanomolar affinity**, and showed that coexpression of A1BG with **CRISP3** (and other CAP/CRISP proteins) can reduce sterol secretion/export by **>50%** in cellular systems; this work situates CRISP proteins within a conserved sterol-binding/export functional axis across CAP-family proteins. |
| GO:0099106 ion channel regulator activity | NAS | NEW | Summary: Term included based on the ShKT/CRISP cysteine-rich C-terminal domain and family-level annotations. Recent direct biochemical work (Miya 2024) shows that human CRISP3 binds the plasma membrane Ca2+ exporter PMCA4b via its N-terminal CAP domain but, in contrast to hCRISP1 and rat CRISP4, did NOT inhibit PMCA4b-mediated Ca2+ extrusion in their assay. This term should therefore be interpreted with caution for CRISP3 specifically; the activity may be paralog-specific. Reason: Core function term not present in existing_annotations. Retained based on the conserved ShKT domain and family activity, but flagged because direct activity on PMCA4b was not observed for hCRISP3 in the only published assay. Supporting Evidence: PMID:37882330 Human CRISP1 (hCRISP1) and hCRISP3 also interacted with PMCA4b via the N-terminal domain. Interestingly, hCRISP1 and rCRISP4 delayed PMCA4b-mediated calcium extrusion but hCRISP3 did not. file:human/CRISP3/CRISP3-deep-research-perplexity-lite.md Ion Channel Regulation: The C-terminal domain is implicated in ion channel regulation, suggesting a role in modulating cellular signaling, especially in reproductive tissues. file:human/CRISP3/CRISP3-uniprot.txt FT DOMAIN 207..240 ShKT (ion channel regulator domain) file:human/CRISP3/CRISP3-deep-research-falcon.md Unlike hCRISP1 and rat CRISP4, **hCRISP3 did not inhibit PMCA4b-mediated Ca2+ extrusion** in their assay system, implying functional divergence among paralogs. |
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)