Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination

Autores
Wang, Jing; Anastasia Gonzalez, Agustin; Bains, Henrietta; Giza, Joanna I.; Clossey, David G.; Deng, Jingjing; Neubert, Thomas A.; Rice, William J.; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons’ growth cones and dendritic spines by interacting directly with the SorCS2 receptor. While it has been reported that the Met66 and Val66 prodomains exhibit only modest differences in structural propensities in the apo state, here we show that Val66 and Met66 prodomains differentially bind zinc (Zn). Zn2+ binds with higher affinity and more broadly impacts residues on the Met66 prodomain compared to the Val66 prodomain as shown by NMR and ITC. Zn2+ binding to the Met66 and Val66 prodomains results in distinct conformational and macroscopic differences observed by NMR, light scattering and cryoEM. To determine if Zn2+ mediated conformational change in the Met66 prodomain is required for biological effect, we mutated His40, a Zn2+ binding site, and observed a loss of Met66 prodomain bioactivity. As the His40 site is distant from the known region of the prodomain involved in receptor binding, we suggest that Met66 prodomain bioactivity involves His40 mediated stabilization of the multimeric structure. Our results point to the necessity of a Zn2+-mediated higher order molecular assembly of the Met66 prodomain to mediate neuronal remodeling.
Fil: Wang, Jing. Weill Cornell Medicine; Estados Unidos
Fil: Anastasia Gonzalez, Agustin. Weill Cornell Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Bains, Henrietta. Weill Cornell Medicine; Estados Unidos
Fil: Giza, Joanna I.. Borough of Manhattan Community College; Estados Unidos
Fil: Clossey, David G.. Weill Cornell Medicine; Estados Unidos
Fil: Deng, Jingjing. New York University. School of Medicine; Estados Unidos
Fil: Neubert, Thomas A.. New York University Langone Health; Estados Unidos
Fil: Rice, William J.. New York University Langone Health; Estados Unidos
Fil: Lee, Francis S.. Weill Cornell Medicine; Estados Unidos
Fil: Hempstead, Barbara L.. Weill Cornell Medicine; Estados Unidos
Fil: Bracken, Clay. Weill Cornell Medicine; Estados Unidos
Materia
BDNF
Prodomain
Zinc
IDP
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:11336/140127
Acceder
id CONICETDig_460f961ef344a6c237ae9c363668452e
oai_identifier_str oai:ri.conicet.gov.ar:11336/140127
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic eliminationWang, JingAnastasia Gonzalez, AgustinBains, HenriettaGiza, Joanna I.Clossey, David G.Deng, JingjingNeubert, Thomas A.Rice, William J.Lee, Francis S.Hempstead, Barbara L.Bracken, ClayBDNFProdomainZincIDPhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons’ growth cones and dendritic spines by interacting directly with the SorCS2 receptor. While it has been reported that the Met66 and Val66 prodomains exhibit only modest differences in structural propensities in the apo state, here we show that Val66 and Met66 prodomains differentially bind zinc (Zn). Zn2+ binds with higher affinity and more broadly impacts residues on the Met66 prodomain compared to the Val66 prodomain as shown by NMR and ITC. Zn2+ binding to the Met66 and Val66 prodomains results in distinct conformational and macroscopic differences observed by NMR, light scattering and cryoEM. To determine if Zn2+ mediated conformational change in the Met66 prodomain is required for biological effect, we mutated His40, a Zn2+ binding site, and observed a loss of Met66 prodomain bioactivity. As the His40 site is distant from the known region of the prodomain involved in receptor binding, we suggest that Met66 prodomain bioactivity involves His40 mediated stabilization of the multimeric structure. Our results point to the necessity of a Zn2+-mediated higher order molecular assembly of the Met66 prodomain to mediate neuronal remodeling.Fil: Wang, Jing. Weill Cornell Medicine; Estados UnidosFil: Anastasia Gonzalez, Agustin. Weill Cornell Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Bains, Henrietta. Weill Cornell Medicine; Estados UnidosFil: Giza, Joanna I.. Borough of Manhattan Community College; Estados UnidosFil: Clossey, David G.. Weill Cornell Medicine; Estados UnidosFil: Deng, Jingjing. New York University. School of Medicine; Estados UnidosFil: Neubert, Thomas A.. New York University Langone Health; Estados UnidosFil: Rice, William J.. New York University Langone Health; Estados UnidosFil: Lee, Francis S.. Weill Cornell Medicine; Estados UnidosFil: Hempstead, Barbara L.. Weill Cornell Medicine; Estados UnidosFil: Bracken, Clay. Weill Cornell Medicine; Estados UnidosRoyal Society of Chemistry2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/140127Wang, Jing; Anastasia Gonzalez, Agustin; Bains, Henrietta; Giza, Joanna I.; Clossey, David G.; et al.; Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination; Royal Society of Chemistry; Metallomics; 12; 8; 8-2020; 1208-12191756-5901CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1039/d0mt00108binfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/metallomics/article/12/8/1208/5967866info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:28Zoai:ri.conicet.gov.ar:11336/140127instacron: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 09:44:28.763CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
title Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
spellingShingle Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
Wang, Jing
BDNF
Prodomain
Zinc
IDP
title_short Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
title_full Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
title_fullStr Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
title_full_unstemmed Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
title_sort Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination
dc.creator.none.fl_str_mv Wang, Jing
Anastasia Gonzalez, Agustin
Bains, Henrietta
Giza, Joanna I.
Clossey, David G.
Deng, Jingjing
Neubert, Thomas A.
Rice, William J.
Lee, Francis S.
Hempstead, Barbara L.
Bracken, Clay
author Wang, Jing
author_facet Wang, Jing
Anastasia Gonzalez, Agustin
Bains, Henrietta
Giza, Joanna I.
Clossey, David G.
Deng, Jingjing
Neubert, Thomas A.
Rice, William J.
Lee, Francis S.
Hempstead, Barbara L.
Bracken, Clay
author_role author
author2 Anastasia Gonzalez, Agustin
Bains, Henrietta
Giza, Joanna I.
Clossey, David G.
Deng, Jingjing
Neubert, Thomas A.
Rice, William J.
Lee, Francis S.
Hempstead, Barbara L.
Bracken, Clay
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BDNF
Prodomain
Zinc
IDP
topic BDNF
Prodomain
Zinc
IDP
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons’ growth cones and dendritic spines by interacting directly with the SorCS2 receptor. While it has been reported that the Met66 and Val66 prodomains exhibit only modest differences in structural propensities in the apo state, here we show that Val66 and Met66 prodomains differentially bind zinc (Zn). Zn2+ binds with higher affinity and more broadly impacts residues on the Met66 prodomain compared to the Val66 prodomain as shown by NMR and ITC. Zn2+ binding to the Met66 and Val66 prodomains results in distinct conformational and macroscopic differences observed by NMR, light scattering and cryoEM. To determine if Zn2+ mediated conformational change in the Met66 prodomain is required for biological effect, we mutated His40, a Zn2+ binding site, and observed a loss of Met66 prodomain bioactivity. As the His40 site is distant from the known region of the prodomain involved in receptor binding, we suggest that Met66 prodomain bioactivity involves His40 mediated stabilization of the multimeric structure. Our results point to the necessity of a Zn2+-mediated higher order molecular assembly of the Met66 prodomain to mediate neuronal remodeling.
Fil: Wang, Jing. Weill Cornell Medicine; Estados Unidos
Fil: Anastasia Gonzalez, Agustin. Weill Cornell Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Bains, Henrietta. Weill Cornell Medicine; Estados Unidos
Fil: Giza, Joanna I.. Borough of Manhattan Community College; Estados Unidos
Fil: Clossey, David G.. Weill Cornell Medicine; Estados Unidos
Fil: Deng, Jingjing. New York University. School of Medicine; Estados Unidos
Fil: Neubert, Thomas A.. New York University Langone Health; Estados Unidos
Fil: Rice, William J.. New York University Langone Health; Estados Unidos
Fil: Lee, Francis S.. Weill Cornell Medicine; Estados Unidos
Fil: Hempstead, Barbara L.. Weill Cornell Medicine; Estados Unidos
Fil: Bracken, Clay. Weill Cornell Medicine; Estados Unidos
description Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons’ growth cones and dendritic spines by interacting directly with the SorCS2 receptor. While it has been reported that the Met66 and Val66 prodomains exhibit only modest differences in structural propensities in the apo state, here we show that Val66 and Met66 prodomains differentially bind zinc (Zn). Zn2+ binds with higher affinity and more broadly impacts residues on the Met66 prodomain compared to the Val66 prodomain as shown by NMR and ITC. Zn2+ binding to the Met66 and Val66 prodomains results in distinct conformational and macroscopic differences observed by NMR, light scattering and cryoEM. To determine if Zn2+ mediated conformational change in the Met66 prodomain is required for biological effect, we mutated His40, a Zn2+ binding site, and observed a loss of Met66 prodomain bioactivity. As the His40 site is distant from the known region of the prodomain involved in receptor binding, we suggest that Met66 prodomain bioactivity involves His40 mediated stabilization of the multimeric structure. Our results point to the necessity of a Zn2+-mediated higher order molecular assembly of the Met66 prodomain to mediate neuronal remodeling.
publishDate 2020
dc.date.none.fl_str_mv 2020-08
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/11336/140127
Wang, Jing; Anastasia Gonzalez, Agustin; Bains, Henrietta; Giza, Joanna I.; Clossey, David G.; et al.; Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination; Royal Society of Chemistry; Metallomics; 12; 8; 8-2020; 1208-1219
1756-5901
CONICET Digital
CONICET
url http://hdl.handle.net/11336/140127
identifier_str_mv Wang, Jing; Anastasia Gonzalez, Agustin; Bains, Henrietta; Giza, Joanna I.; Clossey, David G.; et al.; Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination; Royal Society of Chemistry; Metallomics; 12; 8; 8-2020; 1208-1219
1756-5901
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1039/d0mt00108b
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/metallomics/article/12/8/1208/5967866
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 Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
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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