Comprehensive Analysis of Reproductive ADAMs: Relationship of ADAM4 and ADAM6 with an ADAM Complex Required for Fertilization in Mice1

Han, Cecil; Choi, Eun‐Young; Park, Inju; Lee, Boyeon; Jin, Sora; Kim, Do Han; Nishimura, Hitoshi; Cho, Chunghee

doi:10.1095/biolreprod.108.073700

Cited by 61 publications

(74 citation statements)

References 34 publications

(104 reference statements)

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“…Misfolded proteins that progress to more distal parts of the secretory pathway can be retrotranslocated to the ER and subjected to ER-associated degradation. An additional layer of the quality control pathway also occurring past the ER is formation of higher order oligomers of certain proteins in the ER- (40,53), with much of the ADAM3 loss occurring during protein transit from the trans-Golgi to the cell surface, such that little or no ADAM3 was detected on the surfaces of Adam2-null cells (54,55). Adam3-null sperm also have reduced amounts of several ADAMs (30,40,53).…”

Section: Discussionmentioning

confidence: 99%

“…An additional layer of the quality control pathway also occurring past the ER is formation of higher order oligomers of certain proteins in the ER- (40,53), with much of the ADAM3 loss occurring during protein transit from the trans-Golgi to the cell surface, such that little or no ADAM3 was detected on the surfaces of Adam2-null cells (54,55). Adam3-null sperm also have reduced amounts of several ADAMs (30,40,53). Protein folding also is important for ADAM stability because Clgn-null sperm lack detectable ADAM1B, ADAM2, and ADAM3; these proteins are lost posttranslationally, probably due to aberrant protein folding due to the Clgn deficiency (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…7C). Interestingly, ADAM2 is still present on Tpst2-null sperm, suggesting that tyrosine O-sulfation by TPST-2 is not required for ADAM2 stability on sperm (40). Nevertheless, the loss of ADAM3 and ADAM6 is suggestive that the sperm surface proteome and sperm membrane functionality could be altered, leading to the abnormalities observed in the Tpst2-null sperm.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the localization of sulfotyrosine residues (Fig. 3) has some overlaps but is not identical to the localization of ADAM6 (40). Examination of how Tpst2 deletion affected ADAM6 and associated ADAMs ADAM3 and ADAM2 provided significant insights.…”

Section: Adam6 and Adam3 Are Not Detected In Sperm From Tpst2mentioning

confidence: 99%

“…ADAM6 forms complexes with two proteins that can participate in sperm-egg interactions, ADAM2 and ADAM3. Additionally, ADAM6 is greatly reduced in sperm lysates from Adam2 and Adam3 knock-out mice (40), and the Adam2 and the Adam3 knock-out mice have deficiencies in sperm migration into the oviduct, sperm-ZP interactions, and sperm-egg membrane interactions (29,30,41). We therefore investigated ADAM6 in more detail.…”

Section: Adam6 and Adam3 Are Not Detected In Sperm From Tpst2mentioning

confidence: 99%

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Lack of Tyrosylprotein Sulfotransferase-2 Activity Results in Altered Sperm-Egg Interactions and Loss of ADAM3 and ADAM6 in Epididymal Sperm

Marcello

Jia

Leary

et al. 2011

Journal of Biological Chemistry

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Tyrosine O-sulfation is a post-translational modification catalyzed by two tyrosylprotein sulfotransferases (TPST-1 and TPST-2) in the trans-Golgi network. Tpst2-deficient mice have male infertility, sperm motility defects, and possible abnormalities in sperm-egg membrane interactions. Studies here show that compared with wild-type sperm, fewer Tpst2-null sperm bind to the egg membrane, but more of these bound sperm progress to membrane fusion. Similar outcomes were observed with wild-type sperm treated with the anti-sulfotyrosine antibody PSG2. The increased extent of sperm-egg fusion is not due to a failure of Tpst2-null sperm to trigger establishment of the egg membrane block to polyspermy. Anti-sulfotyrosine staining of sperm showed localization similar to that of IZUMO1, a sperm protein that is essential for gamete fusion, but we detected little to no tyrosine sulfation of IZUMO1 and found that IZUMO1 expression and localization were normal in Tpst2-null sperm. Turning to a discovery-driven approach, we used mass spectrometry to characterize sperm proteins that associated with PSG2. This identified ADAM6, a member of the A disintegrin and A metalloprotease (ADAM) family; members of this protein family are associated with multiple sperm functions. Subsequent studies revealed that Tpst2-null sperm lack ADAM6 and ADAM3. Loss of ADAM3 is strongly associated with male infertility and is observed in knockouts of male germ line-specific endoplasmic reticulum-resident chaperones, raising the possibility that TPST-2 may function in quality control in the secretory pathway. These data suggest that TPST-2-mediated tyrosine O-sulfation participates in regulating the sperm surface proteome or membrane order, ultimately affecting male fertility.Tyrosine O-sulfation is a post-translational modification catalyzed by tyrosylprotein sulfotransferases (TPSTs) 3 (1).Although tyrosine O-sulfation was first described more than 50 years ago (2), the TPSTs were identified just a decade ago (3-5). Tyrosine-sulfated proteins and/or TPST activity have been observed in animals and plants but not in prokaryotes or fungi (1, 6). Most animals' genomes appear to have two genes encoding TPSTs, although only one Tpst gene has been identified in Drosophila (1, 6); a TPST also has recently been identified in Arabidopsis (7). The mammalian enzymes are known as TPST-1 and TPST-2; these two enzymes are broadly expressed in human and murine tissues and are co-expressed in the majority of cell types (1). Tyrosine O-sulfation occurs in the trans-Golgi network, with the luminally oriented catalytic domains of TPSTs mediating the transfer of sulfate from the universal sulfate donor 3Ј-phosphoadenosine 5Ј-phosphosulfate to tyrosine residues in polypeptides (3-5, 8 -10). TPST substrates include a variety of secreted and membrane-anchored proteins, including adhesion molecules, G-protein-coupled receptors, and extracellular matrix proteins. Tyrosine O-sulfation is implicated in protein-protein interactions and in optimization of protein function (1, 11)...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Adam6 and Adam3 Are Not Detected In Sperm From Tpst2mentioning

confidence: 99%

Section: Adam6 and Adam3 Are Not Detected In Sperm From Tpst2mentioning

confidence: 99%

See 3 more Smart Citations

Lack of Tyrosylprotein Sulfotransferase-2 Activity Results in Altered Sperm-Egg Interactions and Loss of ADAM3 and ADAM6 in Epididymal Sperm

Marcello

Jia

Leary

et al. 2011

Journal of Biological Chemistry

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Identification of heat shock protein 5, calnexin and integral membrane protein 2B as Adam7‐interacting membrane proteins in mouse sperm

Han

Park

Lee

et al. 2011

Journal Cellular Physiology

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In mammals, sperm acquire their motility and ability to fertilize eggs in the epididymis. This maturation process involves the acquisition of particular proteins from the epididymis. One such secretory protein specifically expressed in the epididymis is Adam7 (a disintegrin and metalloprotease 7). Previous studies have shown that Adam7 that resides in an intracellular compartment of epididymal cells is transferred to sperm membranes, where its levels are dependent on the expression of Adam2 and Adam3, which have critical roles in fertilization. Here, using a proteomics approach based on mass spectrometry, we identified proteins that interact with Adam7 in sperm membranes. This analysis revealed that Adam7 forms complexes with calnexin (Canx), heat shock protein 5 (Hspa5), and integral membrane protein 2B (Itm2b). Canx and Hspa5 are molecular chaperones, and Itm2b is a type II integral membrane protein implicated in neurodegeneration. The interaction of Adam7 with these proteins was confirmed by immunoprecipitation-Western blot analysis. We found that Adam7 and Itm2b are located in detergent-resistant regions known to be highly correlated with membrane lipid rafts. We further found that the association of Adam7 with Itm2b is remarkably promoted during sperm capacitation owing to a conformational change of Adam7 that occurs in concert with the capacitation process. Thus, our results suggest that Adam7 functions in fertilization through the formation of a chaperone complex and enhanced association with Itm2b during capacitation in sperm.

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Male fertility in Mus musculus requires the activity of TRYX5 in sperm migration into the oviduct

Zhang

Cui

et al. 2020

Journal Cellular Physiology

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Nowadays, abnormal loss of serine proteases appears very frequently in male patients with unexplained sterility. In fact, many testis-specific serine proteases, the largest family among the four protease families implicated in murine spermatogenesis, are indispensable for reproduction. In the present study, we demonstrate that the previously uncharacterized testis-specific serine protease TRYX5 (1700074P13Rik) is required for male fertility in mice. Tryx5 −/− male mice are sterile, yet they have normal spermatogenesis and normal sperm parameters. In vivo fertilization experiments showed that the fertilization rate of Tryx5 −/− sperm was almost zero. Sperm counting and analysis of paraffin sections of oviducts revealed that Tryx5 −/− sperm were unable to migrate into the oviduct, which is likely the cause of the observed infertility of the Tryx5 −/− male mice. Importantly, we also found that there was almost no mature ADAM3 present in Tryx5 −/− sperm and almost no ADAM3 precursor in Tryx5 −/− elongated spermatids of S13-16 stage, even though testes of Tryx5 −/− and wild type mice had the same amount of the total precursor ADAM3. Collectively, our results demonstrate that Tryx5 is essential for male fertility in mice and suggest that TRYX5 functions in the stability or localization of ADAM3 precursor in elongated spermatids S13-16 stage, thereby regulating the ability of sperm to migrate from the uterus into the ampulla of the oviduct, the site of fertilization. K E Y W O R D Sknockout mouse, male infertility, sperm migration, Tryx5

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Comprehensive Analysis of Reproductive ADAMs: Relationship of ADAM4 and ADAM6 with an ADAM Complex Required for Fertilization in Mice1

Cited by 61 publications

References 34 publications

Lack of Tyrosylprotein Sulfotransferase-2 Activity Results in Altered Sperm-Egg Interactions and Loss of ADAM3 and ADAM6 in Epididymal Sperm

Lack of Tyrosylprotein Sulfotransferase-2 Activity Results in Altered Sperm-Egg Interactions and Loss of ADAM3 and ADAM6 in Epididymal Sperm

Identification of heat shock protein 5, calnexin and integral membrane protein 2B as Adam7‐interacting membrane proteins in mouse sperm

Male fertility in Mus musculus requires the activity of TRYX5 in sperm migration into the oviduct

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