Use of the ND evidence code for Gene Ontology (GO) terms
Transcripts encoding the sperm surface protein tMDC II are non-functional in the human.
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Every characterised human tMDC II (ADAM5) transcript is non-functional, carrying deletions and in-frame termination codons relative to the macaque orthologue, and no protein is detected on Western blots of human testis or sperm extract with a macaque anti-tMDC II antiserum.
"all of which are also non-functional owing to the presence of deletions and in-frame termination codons, when compared with the macaque orthologue, a finding which is further supported by the lack of immunoreactivity on Western blots of human testis and sperm extracts probed with a macaque anti-tMDC II polyclonal antiserum"
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The loss is not isolated: two other sperm MDC proteins of the same clade, fertilin alpha and tMDC I, had already been shown to be non-functional in humans.
"Of these, two (fertilin alpha and tMDC I) have recently been shown to be non-functional in the human."
ADAM5 is required for sperm-zona pellucida binding and sperm oviduct migration†.
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Mouse Adam5 knockouts are severely subfertile with structurally normal, motile sperm that fail to transit the uterotubal junction and bind the zona pellucida poorly.
"Adam5 KO sperm failed to transit the uterotubal junction (UTJ) and displayed severe defects in zona pellucida (ZP) binding, phenotypes that resemble those observed in Adam2 and Adam3 knockout mice."
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ADAM5 acts through complex membership rather than catalysis: its loss reduces ADAM2 and ADAM3 protein levels on spermatozoa.
"Western blot analysis revealed a significant reduction in the levels of ADAM2 and ADAM3 in Adam5 KO spermatozoa, supporting the previous finding that ADAM5 interacts with these proteins to form a complex."
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The authors state explicitly that ADAM5 is a pseudogene in humans, bounding the transfer of their mouse results.
"While ADAM5 is a pseudogene in humans, our results provide valuable insights into the function of ADAM family proteins in mammalian reproduction."
Association of Inherited Copy Number Variation in ADAM3A and ADAM5 Pseudogenes with Oropharynx Cancer Risk and Outcome.
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The ADAM5 pseudogene transcript is proposed to act as a competing endogenous RNA for miR-122b-5p through homology to the ADAM9 3'-UTR - a predicted binding site, not a measured interaction.
"ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p."
Testicular and epididymal ADAMs: expression and function during fertilization.
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Sperm ADAMs assemble into defined complexes, ADAM2-ADAM3-ADAM5 among them, placing the ancestral ADAM5 function in adhesion complex assembly rather than proteolysis.
"Some of these sperm ADAMs are assembled into potentially functional complexes, including ADAM1B-ADAM2, ADAM2-ADAM3-ADAM4, ADAM2-ADAM3-ADAM5, and ADAM2-ADAM3-ADAM6."
The MDC family of proteins and their processing during epididymal transit.
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In macaque, tMDC II is localised to spermatogenic cells and processed during epididymal transit, retaining its disintegrin domain on mature spermatozoa.
"we have localized a number of these MDC proteins (fertilin alpha, fertilin beta, tMDC I, tMDC II and tMDC III) to spermatogenic cells and demonstrated that they are processed as spermatozoa pass through the epididymis"
Lactadherin is a candidate oviduct Lewis X trisaccharide receptor on porcine spermatozoa.
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Porcine ADAM5 was identified by LC-MS/MS as one of two sperm plasma membrane proteins binding sulfated Lewis X, indicating a carbohydrate-adhesion role for the intact orthologue.
"that bound sulfated Lewis X, ADAM5, which spermatozoa, was confidently identified"
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
ADAM5 (human, Q6NVV9) — catalytic-motif, ortholog-length and GO-census analysis
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The 412-residue human putative translation contains no HExxHxxGxxHD zinc-binding motif and no HExxH core at all, while ADAM10, ADAM17, ADAM9 and ADAM19 all return an intact motif - so the scan discriminates rather than simply failing to find anything.
"Human ADAM5 contains **no `HExxH` substring anywhere in its 412 residues**."
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Aligned to macaque ADAM5, the human sequence shows a single 246-residue internal deletion, and the signal peptide, Peptidase M12B domain and transmembrane helix are all lost while the propeptide, disintegrin and EGF-like regions are retained.
"the **signal peptide** and the **transmembrane helix** are lost outright, and the disintegrin domain is itself truncated because the deletion cuts through it"
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Measured over all 331 Swiss-Prot reviewed members of PANTHER PTHR11905 (the reviewed subset of a 29,886-protein family), 37 of the 40 members that have the Peptidase M12B fold but no HExxH zinc core still carry GO:0004222, against 204 of 204 for members with the site intact - so the annotation does not discriminate on the catalytic site.
"Losing the zinc-binding site has almost no effect on whether a reviewed family member is annotated with metalloendopeptidase activity"
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The catalytic over-annotation the family invites is present on ADAM5's orthologues and coding paralogues but not on human ADAM5, because the pipelines key on presence of the M12B fold rather than on integrity of the zinc site.
"The pipelines that place `GO:0004222` on this clade key on **presence of the M12B fold, not on integrity of the zinc site**, so every close relative of ADAM5 that retains the fold receives the activity term despite lacking the catalytic residues."
UniProt entry Q6NVV9 (ADAM5_HUMAN)
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UniProt assigns protein existence level 5 (Uncertain) and cautions that ADAM5 could be a pseudogene product not expected to have protease activity.
"CAUTION: Could be the product of a pseudogene. Not expected to have"
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No evolutionary-model annotations exist for this entry, confirming the absence of IBA annotations independently of the worklist.
"DR PAN-GO; Q6NVV9; 0 GO annotations based on evolutionary models."