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Lessons on protein structure from interleukin‐4: All disulfides are not created equal

2023Journal article Open access
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dc.contributor.authorVaz, Daniela C.
dc.contributor.authorRodrigues, J. Rui
dc.contributor.authorLoureiro‐Ferreira, Nuno
dc.contributor.authorMĂźller, Thomas D.
dc.contributor.authorSebald, Walter
dc.contributor.authorRedfield, Christina
dc.contributor.authorBrito, Rui M. M.
dc.date.accessioned2024-05-31T17:00:36Z
dc.date.available2024-05-31T17:00:36Z
dc.date.issued2023
dc.descriptionAcknowledgments: European Regional Development Fund; Fundaçao para a Ciência e a Tecnologia, ˜Grant/Award Numbers: UIDB/00313/2020, UIDP/00313/2020; FEDER/COMPETE, Grant/Award Numbers: CENTRO07-CT62-FEDER-002012, RECI/QEQQFI/0168/2012; Rede Nacional de Ressonância Magnética Nuclear (RNRMN/PTNMR); ALiCE, Grant/Award Number: LA/P/0045/2020; LSRE-LCM, Grant/Award Numbers: UIDP/50020/2020, UIDB/50020/2020; FCT/MCTES (PIDDAC).pt_PT
dc.description.abstractInterleukin-4 (IL-4) is a hematopoietic cytokine composed by a four-helix bundle stabilized by an antiparallel beta-sheet and three disulfide bonds: Cys3-Cys127, Cys24-Cys65, and Cys46-Cys99. IL-4 is involved in several immune responses associated to infection, allergy, autoimmunity, and cancer. Besides its physiological relevance, IL-4 is often used as a “model” for protein design and engineering. Hence, to understand the role of each disulfide in the structure and dynamics of IL-4, we carried out several spectroscopic analyses (circular dichroism [CD], fluorescence, nuclear magnetic resonance [NMR]), and molecular dynamics (MD) simulations on wild-type IL-4 and four IL-4 disulfide mutants. All disulfide mutants showed loss of structure, altered interhelical angles, and looser core packings, showing that all disulfides are relevant for maintaining the overall fold and stability of the four-helix bundle motif, even at very low pH. In the absence of the disulfide connecting both protein termini Cys3-Cys127, C3T-IL4 showed a less packed protein core, loss of secondary structure ( 9%) and fast motions on the sub-nanosecond time scale (lower S2 order parameters and larger τc correlation time), especially at the two protein termini, loops, beginning of helix A and end of helix D. In the absence of Cys24-Cys65, C24T-IL4 presented shorter alpha-helices (14% loss in helical content), altered interhelical angles, less propensity to form the small anti-parallel beta-sheet and increased dynamics. Simultaneously deprived of two disulfides (Cys3-Cys127 and Cys24-Cys65), IL-4 formed a partially folded “molten globule” with high 8-anilino1-naphtalenesulphonic acid-binding affinity and considerable loss of secondary structure ( 50%decrease), as shown by the far UV-CD, NMR, and MD data.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationVaz DC, Rodrigues JR, Loureiro-Ferreira N, et al. Lessons on protein structure from interleukin-4: All disulfides are not created equal. Proteins. 2023;1‐17. https://doi.org/10.1002/prot.26611pt_PT
dc.identifier.doihttps://doi.org/10.1002/prot.26611pt_PT
dc.identifier.eissn1097-0134
dc.identifier.urihttp://hdl.handle.net/10400.8/9695
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationCENTRO07-CT62-FEDER-002012pt_PT
dc.relationCoimbra Chemistry Center
dc.relationCoimbra Chemistry Center
dc.relationLaboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials
dc.relationLaboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/10.1002/prot.26611pt_PT
dc.subject5N NMR relaxationpt_PT
dc.subjectDisulfide bondspt_PT
dc.subjectFour-helix bundlept_PT
dc.subjectInterleukin-4pt_PT
dc.subjectMolecular dynamics simulationspt_PT
dc.subjectRDC-refined NMR solution structurespt_PT
dc.titleLessons on protein structure from interleukin‐4: All disulfides are not created equalpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleLaboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials
oaire.awardTitleLaboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00313%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00313%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F50020%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F50020%2F2020/PT
oaire.citation.endPage235pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage219pt_PT
oaire.citation.titleProteins: Structure, Function, and Bioinformaticspt_PT
oaire.citation.volume92pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameBarroso de Moura Cipreste Vaz
person.familyNameRodrigues
person.givenNameDaniela
person.givenNameJoaquim Rui
person.identifier.ciencia-id801A-7761-328C
person.identifier.ciencia-id9018-0B83-E2C6
person.identifier.orcid0000-0001-7562-4676
person.identifier.orcid0000-0002-9756-1124
person.identifier.ridR-5243-2017
person.identifier.ridL-4137-2014
person.identifier.scopus-author-id6602838931
person.identifier.scopus-author-id10242931100
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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