PCSK4-null sperm display enhanced protein tyrosine phosphorylation and ADAM2 proteolytic processing during in vitro capacitation

Gyamera-Acheampong, Charles; Vasilescu, Julian; Figeys, Daniel; Mbikay, Majambu

doi:10.1016/j.fertnstert.2008.12.013

Cited by 11 publications

(5 citation statements)

References 61 publications

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“…The furin inhibitors we used were able to inhibit multiple PCSK activities (59 -62), so future studies will be needed to identify the specific protease(s) responsible for cleavage and activation of PLB. Recently, a study using mutant mice demonstrated that PCSK4 localizes to the sperm APM and proteolytically cleaves ADAM2 in response to sterol removal (63,64), positioning it appropriately for this role.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Asano

Nelson-Harrington

Travis

2013

Journal of Biological Chemistry

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Background: How sperm sterol removal enables acrosome exocytosis (AE) is unclear; phospholipase B (PLB) is enriched in sperm membrane rafts. Results: Sterol removal leads to proteolytic activation of PLB, stimulating the initiation of changes leading to AE. Conclusion: PLB activation plays an important role in fertilization. Significance: We identify a mechanism for how sterol removal enables AE, consistent with new, zona pellucida-independent models for membrane fusion.

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Section: Discussionmentioning

confidence: 99%

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Asano

Nelson-Harrington

Travis

2013

Journal of Biological Chemistry

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“…Furthermore, mice lacking proprotein convertase 4, a testis-specifi c convertase, exhibit fertility defects including reduced zona pellucid binding suggesting a role for PCSK4 in fertilization [ 74 ]. Spermatozoa from PSCK4 null mice showed increased ADAM2 processing possibly refl ecting the upregulation of PCSK7 activity in response to the loss of PCSK4, supporting a role for proprotein convertases in ADAM protein processing [ 75 ]. Furthermore, exposure of spermatozoa to a peptide inhibitor of PCSK4 resulted in decreased ADAM2 processing [ 76 ].…”

Section: Protein Processingmentioning

confidence: 99%

Role of Posttranslational Protein Modifications in Epididymal Sperm Maturation and Extracellular Quality Control

Cornwall

2014

Advances in Experimental Medicine and Biology

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The epididymal lumen is a complex microenvironment in which spermatozoa acquire motility and fertility. Spermatozoa are synthetically inactive and therefore the maturation process requires their interaction with proteins that are synthesized and secreted in a highly regionalized manner by the epididymal epithelium. In addition to the integration of epididymal secretory proteins, posttranslational modifications of existing sperm proteins are important for sperm maturation and acquisition of fertilizing potential. Phosphorylation, glycosylation, and processing are several of the posttranslational modifications that sperm proteins undergo during epididymal transit resulting in changes in protein function and localization ultimately leading to mature spermatozoa. In addition to these well-characterized modifications, protein aggregation and cross-linking also occur within the epididymal lumen and may represent unique mechanisms for controlling protein function including that for maturation as well as for extracellular quality control.

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“…Synthetic peptides encompassing these cleavage motifs were hydrolyzed by recPC4 (Basak et al, 2004). Significantly, ADAM2 has been shown to be processed in vivo, from the molecular mass of 100 kDa in testicular germ cells to 45 kDa in mature caudal epididymal sperm and then to 27 kDa following capacitation (Gyamera‐Acheampong et al, 2010). In this report, we confirmed this processing event of ADAM2 and we showed for the first time that this processing involved the removal of the C‐terminal region of the 45 kDa form (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…PCSKs cleave protein substrates at the carboxy terminal of an Arg residue (P1 position) within the sequence motif: R/K − (X) n − X/K/R − R↓ (X = any amino acid except Cys; n is equal to 1, 3 or 5; K and R are preferred P2 amino acids) (Seidah and Chretien, 1999; Scamuffa et al, 2006; Chretien et al, 2008). Among the nine members of the PCSK family, PCSK4 (also called proprotein convertase (PC)4) is known for its selective expression in male germ cells (Mbikay et al, 1994, 1997; Gyamera‐Acheampong et al, 2006, 2010), although it is also expressed in the ovary (Tadros et al, 2001), placenta (Qiu et al, 2005) and oocytes (St Germain et al, 2005). The physiological significance of PCSK4 has been revealed in Pcsk4‐ null male mice, which are severely subfertile (Mbikay et al, 1997; Gyamera‐Acheampong et al, 2006).…”

mentioning

confidence: 99%

Enzymatic activity of sperm proprotein convertase is important for mammalian fertilization

Iamsaard

Vanichviriyakit

Hommalai

et al. 2011

Journal Cellular Physiology

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Proprotein convertase subtilisin/kexin 4 (PCSK4) is implicated for sperm fertilizing ability, based on studies using Pcsk4-null mice. Herein we demonstrated proprotein convertase (PC) activity in intact sperm and acrosomal vesicles. To determine whether this activity was important for sperm fertilizing ability, a peptide inhibitor was designed based on PCSK4 prodomain sequence (proPC4(75-90)), which contains its primary autocatalytic cleavage site. ProPC4(75-90) inhibited recombinant PCSK4's activity with a K(i) value of 5.4 µM, and at 500 µM, it inhibited sperm PC activity almost completely. Treatment of sperm with proPC4(75-90) inhibited their egg fertilizing ability in a dose dependent manner. Correlation between sperm PC activity and fertilizing ability showed a high co-efficient value (>0.9), indicating the importance of sperm PC activity in fertilization. In particular, sperm PC activity was important for capacitation and zona pellucida (ZP)-induced acrosome reaction, since proPC4(75-90) -treated sperm showed markedly decreased rates in these two events. These results were opposite to those observed in Pcsk4-null sperm, which contained higher PC activity than wild type sperm, possibly due to overcompensation by PCSK7, the other PCSK enzyme found in sperm. ADAM2 (45 kDa), a sperm plasma membrane protein, involved in sperm-egg plasma membrane interaction, was also processed into a smaller form (27 kDa) during capacitation at a much reduced level in proPC4(75-90) -treated sperm. This result suggested that ADAM2 may be a natural substrate of sperm PCSK4 and its cleavage by the enzyme during acrosome reaction may be relevant to the fertilization process.

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PCSK4-null sperm display enhanced protein tyrosine phosphorylation and ADAM2 proteolytic processing during in vitro capacitation

Cited by 11 publications

References 61 publications

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Role of Posttranslational Protein Modifications in Epididymal Sperm Maturation and Extracellular Quality Control

Enzymatic activity of sperm proprotein convertase is important for mammalian fertilization

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