دورية أكاديمية
Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: repercussions for male contraceptive development.
| العنوان: | Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: repercussions for male contraceptive development. |
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| المؤلفون: | Silva AAS; Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil., Raimundo TRF; Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil., Mariani NAP; Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil., Kushima H; Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil., Avellar MCW; Department of Pharmacology, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo-SP, Brazil., Buffone MG; Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina., Paula-Lopes FF; Department of Biological Sciences, Universidade Federal de São Paulo-Campus Diadema, Diadema-SP, Brazil., Moura MT; Department of Biological Sciences, Universidade Federal de São Paulo-Campus Diadema, Diadema-SP, Brazil., Silva EJR; Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil. |
| المصدر: | Molecular human reproduction [Mol Hum Reprod] 2021 Nov 27; Vol. 27 (12). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press for the European Society for Human Reproduction and Embryology Country of Publication: England NLM ID: 9513710 Publication Model: Print Cited Medium: Internet ISSN: 1460-2407 (Electronic) Linking ISSN: 13609947 NLM ISO Abbreviation: Mol Hum Reprod Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press for the European Society for Human Reproduction and Embryology Original Publication: Oxford, UK : Published for the European Society for Human Reproduction and Embryology by Oxford University Press, [1995- |
| مواضيع طبية MeSH: | Drug Design*, Antibodies/*pharmacology , Contraceptive Agents, Male/*pharmacology , Proteinase Inhibitory Proteins, Secretory/*antagonists & inhibitors , Sperm Capacitation/*drug effects , Sperm Motility/*drug effects , Spermatozoa/*drug effects, Animals ; Binding Sites ; Biomechanical Phenomena ; Epitopes ; Female ; Ligands ; Male ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Phosphorylation ; Protein Binding ; Protein Interaction Domains and Motifs ; Proteinase Inhibitory Proteins, Secretory/chemistry ; Proteinase Inhibitory Proteins, Secretory/metabolism ; Spermatozoa/metabolism ; Tyrosine ; Mice |
| مستخلص: | EPPIN (epididymal protease inhibitor) is a mammalian conserved sperm-binding protein displaying an N-terminal WFDC (whey-acidic protein four-disulfide core) and a C-terminal Kunitz protease inhibitor domains. EPPIN plays a key role in regulating sperm motility after ejaculation via interaction with the seminal plasma protein SEMG1 (semenogelin-1). EPPIN ligands targeting the SEMG1 binding site in the Kunitz domain are under development as male contraceptive drugs. Nevertheless, the relative contributions of EPPIN WFDC and Kunitz domains to sperm function remain obscure. Here, we evaluated the effects of antibodies targeting specific epitopes in EPPIN's WFDC (Q20E antibody, Gln20-Glu39 epitope) and Kunitz (S21C and F21C antibodies, Ser103-Cys123 and Phe90-C110 epitopes, respectively) domains on mouse sperm motility and fertilizing ability. Computer-assisted sperm analysis showed that sperm co-incubation with S21C antibody (but not F21C antibody) lowered progressive and hyperactivated motilities and impaired kinematic parameters describing progressive (straight-line velocity; VSL, average path velocity; VAP and straightness; STR) and vigorous sperm movements (curvilinear velocity; VCL, amplitude of lateral head movement; ALH, and linearity; LIN) compared with control. Conversely, Q20E antibody-induced milder inhibition of progressive motility and kinematic parameters (VAP, VCL and ALH). Sperm co-incubation with S21C or Q20E antibodies affected in vitro fertilization as revealed by reduced cleavage rates, albeit without changes in capacitation-induced tyrosine phosphorylation. In conclusion, we show that targeting specific epitopes in EPPIN Kunitz and WFDC domains inhibits sperm motility and capacitation-associated events, which decrease their fertilizing ability; nevertheless, similar observations in vivo remain to be demonstrated. Simultaneously targeting residues in S21C and Q20E epitopes is a promising approach for the rational design of EPPIN-based ligands with spermostatic activity. (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: capacitation; drug target; fertilization; hyperactivation; male contraception; sperm motility; spermatozoon |
| المشرفين على المادة: | 0 (Antibodies) 0 (Contraceptive Agents, Male) 0 (Epitopes) 0 (Ligands) 0 (Proteinase Inhibitory Proteins, Secretory) 0 (eppin protein, mouse) 42HK56048U (Tyrosine) |
| تواريخ الأحداث: | Date Created: 20211118 Date Completed: 20220303 Latest Revision: 20240226 |
| رمز التحديث: | 20240226 |
| DOI: | 10.1093/molehr/gaab066 |
| PMID: | 34792600 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2407 |
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| DOI: | 10.1093/molehr/gaab066 |