Base de dados : MEDLINE
Pesquisa : G02.111.570.820.709.275.750.125 [Categoria DeCS]
Referências encontradas : 4 [refinar]
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[PMID]:28270562
[Au] Autor:Nomikos M; Stamatiadis P; Sanders JR; Beck K; Calver BL; Buntwal L; Lofty M; Sideratou Z; Swann K; Lai FA
[Ad] Endereço:College of Medicine, Qatar University, PO Box 2713, Doha, Qatar mixosn@yahoo.com lait@cf.ac.uk.
[Ti] Título:Male infertility-linked point mutation reveals a vital binding role for the C2 domain of sperm PLCζ.
[So] Source:Biochem J;474(6):1003-1016, 2017 Mar 07.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sperm-specific phospholipase C zeta (PLCζ) is widely considered to be the physiological stimulus that evokes intracellular calcium (Ca ) oscillations that are essential for the initiation of egg activation during mammalian fertilisation. A recent genetic study reported a male infertility case that was directly associated with a point mutation in the PLCζ C2 domain, where an isoleucine residue had been substituted with a phenylalanine (I489F). Here, we have analysed the effect of this mutation on the Ca oscillation-inducing activity and the biochemical properties of human PLCζ. Microinjection of cRNA or recombinant protein corresponding to PLCζ mutant at physiological concentrations completely failed to cause Ca oscillations and trigger development. However, this infertile phenotype could be effectively rescued by microinjection of relatively high (non-physiological) amounts of recombinant mutant PLCζ protein, leading to Ca oscillations and egg activation. Our biochemical analysis suggested that the PLCζ mutant displayed similar enzymatic properties, but dramatically reduced binding to PI(3)P and PI(5)P-containing liposomes compared with wild-type PLCζ. Our findings highlight the importance of PLCζ at fertilisation and the vital role of the C2 domain in PLCζ function, possibly due to its novel binding characteristics.
[Mh] Termos MeSH primário: Domínios C2
Cálcio/metabolismo
Infertilidade Masculina/genética
Fosfoinositídeo Fosfolipase C/química
Mutação Puntual
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Sinalização do Cálcio
Bovinos
Feminino
Fertilização
Expressão Gênica
Seres Humanos
Isoleucina/química
Isoleucina/metabolismo
Lipossomos/química
Lipossomos/metabolismo
Masculino
Camundongos
Microinjeções
Oócitos/citologia
Oócitos/metabolismo
Fenilalanina/química
Fenilalanina/metabolismo
Fosfatos de Fosfatidilinositol/química
Fosfatos de Fosfatidilinositol/metabolismo
Fosfoinositídeo Fosfolipase C/genética
Fosfoinositídeo Fosfolipase C/metabolismo
Ligação Proteica
RNA Complementar/administração & dosagem
RNA Complementar/genética
RNA Complementar/metabolismo
Proteínas Recombinantes/administração & dosagem
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Espermatozoides/metabolismo
Espermatozoides/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Liposomes); 0 (Phosphatidylinositol Phosphates); 0 (RNA, Complementary); 0 (Recombinant Proteins); 04Y7590D77 (Isoleucine); 47E5O17Y3R (Phenylalanine); EC 3.1.4.11 (PLCZ1 protein, human); EC 3.1.4.11 (Phosphoinositide Phospholipase C); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161057


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[PMID]:27758819
[Au] Autor:Gangadharan B; Ing M; Delignat S; Peyron I; Teyssandier M; Kaveri SV; Lacroix-Desmazes S
[Ad] Endereço:Sorbonne Universités, UPMC Université Paris 06, UMR S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
[Ti] Título:The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells.
[So] Source:Haematologica;102(2):271-281, 2017 Feb.
[Is] ISSN:1592-8721
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:The development of inhibitory antibodies to therapeutic factor VIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-factor VIII immune response is factor VIII interaction with receptor(s) on antigen-presenting cells, followed by endocytosis and presentation to naïve CD4 T cells. Recent studies indicate a role for the C1 domain in factor VIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic factor VIII uptake. Co-incubation of factor VIII with BO2C11, a monoclonal C2-specific immunoglobulin G, reduced factor VIII endocytosis by dendritic cells and presentation to CD4 T cells, and diminished factor VIII immunogenicity in factor VIII-deficient mice. The mutation of basic residues within the BO2C11 epitope of C2 replicated reduced in vitro immunogenic uptake, but failed to prevent factor VIII immunogenicity in mice. BO2C11 prevents factor VIII binding to von Willebrand factor, thus potentially biasing factor VIII immunogenicity by perturbing its half-life. Interestingly, a factor VIII mutant, that does not bind von Willebrand factor, demonstrated unaltered endocytosis by dendritic cells as well as immunogenicity in factor VIII-deficient mice. Co-incubation of factor VIII with BO2C11, however, resulted in decreased factor VIII immunogenicity in vivo In addition, a previously described triple C1 mutant showed decreased uptake in vitro, and reduced immunogenicity in vivo, but only in the absence of endogenous von Willebrand factor. Taken together, the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity.
[Mh] Termos MeSH primário: Domínios C2
Células Dendríticas/imunologia
Células Dendríticas/metabolismo
Endocitose/imunologia
Fator VIII/imunologia
Fator VIII/metabolismo
Domínios Proteicos
[Mh] Termos MeSH secundário: Animais
Células Apresentadoras de Antígenos/imunologia
Células Apresentadoras de Antígenos/metabolismo
Fator VIII/química
Fator VIII/genética
Técnicas de Inativação de Genes
Hemofilia A/genética
Hemofilia A/imunologia
Hemofilia A/metabolismo
Seres Humanos
Ativação Linfocitária/imunologia
Camundongos
Mutação
Ligação Proteica
Subpopulações de Linfócitos T/imunologia
Subpopulações de Linfócitos T/metabolismo
Fator de von Willebrand/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (von Willebrand Factor); 9001-27-8 (Factor VIII)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.3324/haematol.2016.148502


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[PMID]:27760353
[Au] Autor:Morales KA; Yang Y; Cole TR; Igumenova TI
[Ad] Endereço:Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas.
[Ti] Título:Dynamic Response of the C2 Domain of Protein Kinase Cα to Ca Binding.
[So] Source:Biophys J;111(8):1655-1667, 2016 Oct 18.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ca -dependent conserved-region 2 (C2) domains target their host signaling proteins to anionic membranes. The Ca -binding event is a prerequisite for membrane association. Here, we investigate multiscale metal-ion-dependent dynamics of the C2 domain of protein kinase Cα (C2α) using NMR spectroscopy. Interactions with metal ions attenuate microsecond-timescale motions of the loop regions, indicating that preorganization of the metal-binding loops occurs before membrane insertion. Binding of a full complement of Ca ions has a profound effect on the millisecond-timescale dynamics of the N- and C-terminal regions of C2α. We propose that Ca binding allosterically destabilizes the terminal regions of C2α and thereby facilitates the conformational rearrangement necessary for full membrane insertion and activation of protein kinase Cα.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Proteína Quinase C-alfa/química
Proteína Quinase C-alfa/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Apoenzimas/química
Apoenzimas/metabolismo
Domínios C2
Ligações de Hidrogênio
Metais/metabolismo
Modelos Moleculares
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Metals); EC 2.7.11.13 (Protein Kinase C-alpha); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE


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[PMID]:26792839
[Au] Autor:Evans CS; He Z; Bai H; Lou X; Jeggle P; Sutton RB; Edwardson JM; Chapman ER
[Ad] Endereço:Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53705-2275 Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705-2275 Molecular and Cellular Pharmacology Program, University of Wisconsin-Madison, Madison, WI 53705-2275.
[Ti] Título:Functional analysis of the interface between the tandem C2 domains of synaptotagmin-1.
[So] Source:Mol Biol Cell;27(6):979-89, 2016 Mar 15.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:C2 domains are widespread motifs that often serve as Ca(2+)-binding modules; some proteins have more than one copy. An open issue is whether these domains, when duplicated within the same parent protein, interact with one another to regulate function. In the present study, we address the functional significance of interfacial residues between the tandem C2 domains of synaptotagmin (syt)-1, a Ca(2+) sensor for neuronal exocytosis. Substitution of four residues, YHRD, at the domain interface, disrupted the interaction between the tandem C2 domains, altered the intrinsic affinity of syt-1 for Ca(2+), and shifted the Ca(2+) dependency for binding to membranes and driving membrane fusion in vitro. When expressed in syt-1 knockout neurons, the YHRD mutant yielded reductions in synaptic transmission, as compared with the wild-type protein. These results indicate that physical interactions between the tandem C2 domains of syt-1 contribute to excitation-secretion coupling.
[Mh] Termos MeSH primário: Domínios C2
Cálcio/metabolismo
Neurônios/metabolismo
Sinaptotagmina I/metabolismo
[Mh] Termos MeSH secundário: Animais
Hipocampo/metabolismo
Hipocampo/fisiologia
Camundongos
Camundongos Knockout
Mutagênese Sítio-Dirigida
Neurônios/fisiologia
Ratos
Transmissão Sináptica
Sinaptotagmina I/química
Sinaptotagmina I/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Synaptotagmin I); 0 (Syt1 protein, rat); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170113
[Lr] Data última revisão:
170113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160122
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E15-07-0503



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