IZUMO4 is the most conserved and least testis-restricted member of the Izumo family. Unlike IZUMO1-3 it has an N-terminal signal peptide but no transmembrane segment, and is a soluble glycoprotein that carries the IZUMO domain. In sperm it is found in the head, where mouse data suggest an intra-acrosomal location because it is largely lost upon the acrosome reaction, and it forms a dimer-sized complex. Antibodies against IZUMO4 reduce human sperm binding and penetration in gamete-interaction assays, but mouse Izumo4 knockout males are fertile, so its biological role remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IZUMO4 is a soluble signal-peptide protein, mapped by UniProt to the secreted compartment. Reason: IZUMO4 lacks a transmembrane domain and is predicted to be soluble and secreted. In sperm it appears to be an intra-acrosomal protein that is lost on the acrosome reaction, i.e. released to the extracellular space as acrosomal content. The extracellular location is plausible, but the main characterized pool is in the acrosome. Supporting Evidence: PMID:19658160 Izumo 1-3 are transmembrane proteins expressed specifically in the testis, and Izumo 4 is a soluble protein expressed in the testis and in other tissues. PMID:19658160 Because Izumo 4 is predicted to be a soluble protein, its loss after the AR suggests it could be an intra-acrosomal protein. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | Summary: Detected in a mass-spectrometry catalogue of isolated human sperm nuclei. Reason: A single proteomic identification in CTAB-isolated sperm nuclei is weak localization evidence. IZUMO4 is a signal-peptide-bearing soluble secretory-pathway protein found in the sperm head acrosomal region; a nuclear (chromatin) location is not supported by any targeted study and likely reflects co-purification of head-associated material. Supporting Evidence: PMID:21630459 With this approach, 403 different proteins have been identified from the isolated sperm nuclei. PMID:40760720 IZUMO proteins were immunolocalized in the acrosomal region of acrosome-intact and acrosome-reacted cells. |
| GO:0016020 membrane | IEA GO_REF:0000117 | REMOVE | Summary: ARBA-based membrane assignment from the Izumo family. Reason: The rule transfers the membrane location of transmembrane family members (IZUMO1-3), but IZUMO4 lacks a transmembrane domain and is a soluble protein. No membrane anchor is predicted; the UniProt record has only a signal peptide. Supporting Evidence: PMID:19658160 On the other hand, Izumo 4 stands out from the other three members because it lacks a transmembrane domain and shows a wider tissue expression. |
| GO:0001669 acrosomal vesicle | IDA PMID:40760720 Uncovering the Role of IZUMO Family Members in Human Fertili... | NEW | Summary: IZUMO4 is detected in the acrosomal region of human sperm and is lost from mouse sperm upon the acrosome reaction. Reason: Human immunolocalization places IZUMO4 in the acrosomal region, and mouse biochemical data indicate a soluble intra-acrosomal pool released by the acrosome reaction. Acrosomal vesicle is proposed rather than acrosomal lumen because the luminal assignment is inferred, not shown. Supporting Evidence: PMID:40760720 IZUMO proteins were immunolocalized in the acrosomal region of acrosome-intact and acrosome-reacted cells. PMID:19658160 Taken together, these results suggest Izumo 4 may be an intra-acrosomal protein |
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Download this section (compressed HTML)Q: Is IZUMO4 a luminal acrosomal protein released at the acrosome reaction, and does it associate with IZUMO1 or JUNO on the sperm or egg surface after release?
Q: What is IZUMO4 doing in somatic tissues where it is also expressed?
Experiment: Immunogold electron microscopy of human sperm before and after the acrosome reaction to define whether IZUMO4 is luminal or membrane-associated, combined with binding assays of recombinant IZUMO4 to JUNO.
Type: localization and binding
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