Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development

Autores
Silva, Alan A. S.; Raimundo, Tamiris R. F.; Mariani, Noemia A. P.; Kushima, Hélio; Avellar, Maria Christina W.; Buffone, Mariano Gabriel; Paula Lopes, Fabíola F.; Moura, Marcelo T.; Silva, Erick J. R.
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Silva, Alan A. S.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Raimundo, Tamiris R. F.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Mariani, Noemia A. P.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Kushima, Hélio. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Avellar, Maria Christina W.. Universidade Federal de Sao Paulo; Brasil
Fil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Paula Lopes, Fabíola F.. Universidade Federal de Sao Paulo; Brasil
Fil: Moura, Marcelo T.. Universidade Federal de Sao Paulo; Brasil
Fil: Silva, Erick J. R.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Materia
CAPACITATION
DRUG TARGET
FERTILIZATION
HYPERACTIVATION
MALE CONTRACEPTION
SPERM MOTILITY
SPERMATOZOON
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/211861
Acceder
id CONICETDig_b34968c1d74fe78a4b2135357ee50afc
oai_identifier_str oai:ri.conicet.gov.ar:11336/211861
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive developmentSilva, Alan A. S.Raimundo, Tamiris R. F.Mariani, Noemia A. P.Kushima, HélioAvellar, Maria Christina W.Buffone, Mariano GabrielPaula Lopes, Fabíola F.Moura, Marcelo T.Silva, Erick J. R.CAPACITATIONDRUG TARGETFERTILIZATIONHYPERACTIVATIONMALE CONTRACEPTIONSPERM MOTILITYSPERMATOZOONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1EPPIN (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.Fil: Silva, Alan A. S.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Raimundo, Tamiris R. F.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Mariani, Noemia A. P.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Kushima, Hélio. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Avellar, Maria Christina W.. Universidade Federal de Sao Paulo; BrasilFil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Paula Lopes, Fabíola F.. Universidade Federal de Sao Paulo; BrasilFil: Moura, Marcelo T.. Universidade Federal de Sao Paulo; BrasilFil: Silva, Erick J. R.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilOxford University Press2021-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/211861Silva, Alan A. S.; Raimundo, Tamiris R. F.; Mariani, Noemia A. P.; Kushima, Hélio; Avellar, Maria Christina W.; et al.; Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development; Oxford University Press; Molecular Human Reproduction; 27; 12; 12-2021; 1-151360-9947CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/molehr/gaab066info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:28Zoai:ri.conicet.gov.ar:11336/211861instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:59:28.496CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
title Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
spellingShingle Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
Silva, Alan A. S.
CAPACITATION
DRUG TARGET
FERTILIZATION
HYPERACTIVATION
MALE CONTRACEPTION
SPERM MOTILITY
SPERMATOZOON
title_short Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
title_full Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
title_fullStr Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
title_full_unstemmed Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
title_sort Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development
dc.creator.none.fl_str_mv Silva, Alan A. S.
Raimundo, Tamiris R. F.
Mariani, Noemia A. P.
Kushima, Hélio
Avellar, Maria Christina W.
Buffone, Mariano Gabriel
Paula Lopes, Fabíola F.
Moura, Marcelo T.
Silva, Erick J. R.
author Silva, Alan A. S.
author_facet Silva, Alan A. S.
Raimundo, Tamiris R. F.
Mariani, Noemia A. P.
Kushima, Hélio
Avellar, Maria Christina W.
Buffone, Mariano Gabriel
Paula Lopes, Fabíola F.
Moura, Marcelo T.
Silva, Erick J. R.
author_role author
author2 Raimundo, Tamiris R. F.
Mariani, Noemia A. P.
Kushima, Hélio
Avellar, Maria Christina W.
Buffone, Mariano Gabriel
Paula Lopes, Fabíola F.
Moura, Marcelo T.
Silva, Erick J. R.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CAPACITATION
DRUG TARGET
FERTILIZATION
HYPERACTIVATION
MALE CONTRACEPTION
SPERM MOTILITY
SPERMATOZOON
topic CAPACITATION
DRUG TARGET
FERTILIZATION
HYPERACTIVATION
MALE CONTRACEPTION
SPERM MOTILITY
SPERMATOZOON
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Silva, Alan A. S.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Raimundo, Tamiris R. F.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Mariani, Noemia A. P.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Kushima, Hélio. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
Fil: Avellar, Maria Christina W.. Universidade Federal de Sao Paulo; Brasil
Fil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Paula Lopes, Fabíola F.. Universidade Federal de Sao Paulo; Brasil
Fil: Moura, Marcelo T.. Universidade Federal de Sao Paulo; Brasil
Fil: Silva, Erick J. R.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/211861
Silva, Alan A. S.; Raimundo, Tamiris R. F.; Mariani, Noemia A. P.; Kushima, Hélio; Avellar, Maria Christina W.; et al.; Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development; Oxford University Press; Molecular Human Reproduction; 27; 12; 12-2021; 1-15
1360-9947
CONICET Digital
CONICET
url http://hdl.handle.net/11336/211861
identifier_str_mv Silva, Alan A. S.; Raimundo, Tamiris R. F.; Mariani, Noemia A. P.; Kushima, Hélio; Avellar, Maria Christina W.; et al.; Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development; Oxford University Press; Molecular Human Reproduction; 27; 12; 12-2021; 1-15
1360-9947
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/molehr/gaab066
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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