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1.
Nature ; 565(7737): 118-121, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30542156

RESUMO

Plasmodium falciparum causes the severe form of malaria that has high levels of mortality in humans. Blood-stage merozoites of P. falciparum invade erythrocytes, and this requires interactions between multiple ligands from the parasite and receptors in hosts. These interactions include the binding of the Rh5-CyRPA-Ripr complex with the erythrocyte receptor basigin1,2, which is an essential step for entry into human erythrocytes. Here we show that the Rh5-CyRPA-Ripr complex binds the erythrocyte cell line JK-1 significantly better than does Rh5 alone, and that this binding occurs through the insertion of Rh5 and Ripr into host membranes as a complex with high molecular weight. We report a cryo-electron microscopy structure of the Rh5-CyRPA-Ripr complex at subnanometre resolution, which reveals the organization of this essential invasion complex and the mode of interactions between members of the complex, and shows that CyRPA is a critical mediator of complex assembly. Our structure identifies blades 4-6 of the ß-propeller of CyRPA as contact sites for Rh5 and Ripr. The limited contacts between Rh5-CyRPA and CyRPA-Ripr are consistent with the dissociation of Rh5 and Ripr from CyRPA for membrane insertion. A comparision of the crystal structure of Rh5-basigin with the cryo-electron microscopy structure of Rh5-CyRPA-Ripr suggests that Rh5 and Ripr are positioned parallel to the erythrocyte membrane before membrane insertion. This provides information on the function of this complex, and thereby provides insights into invasion by P. falciparum.


Assuntos
Antígenos de Protozoários/ultraestrutura , Proteínas de Transporte/ultraestrutura , Microscopia Crioeletrônica , Complexos Multiproteicos/química , Complexos Multiproteicos/ultraestrutura , Plasmodium falciparum , Proteínas de Protozoários/ultraestrutura , Animais , Antígenos de Protozoários/química , Antígenos de Protozoários/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Drosophila , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/parasitologia , Humanos , Modelos Moleculares , Complexos Multiproteicos/metabolismo , Plasmodium falciparum/química , Plasmodium falciparum/patogenicidade , Plasmodium falciparum/ultraestrutura , Ligação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo
2.
Sci Signal ; 13(636)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546545

RESUMO

Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the underlying mechanism involved and the basis for SMCHD1 homodimerization are unclear. Here, we used x-ray crystallography to solve the three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we defined structural features of the hinge domain that participated in homodimerization and nucleic acid binding, and we identified a functional hotspot required for chromatin localization in cells. This structure provides a template for interpreting the mechanism by which patient polymorphisms within the SMCHD1 hinge domain could compromise function and lead to facioscapulohumeral muscular dystrophy.


Assuntos
Proteínas Cromossômicas não Histona/química , Multimerização Proteica , Animais , Proteínas Cromossômicas não Histona/genética , Cristalografia por Raios X , Camundongos , Ácidos Nucleicos/química , Ácidos Nucleicos/metabolismo , Domínios Proteicos , Estrutura Quaternária de Proteína , Irmãos
3.
Cancer Cell ; 29(2): 145-58, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26859455

RESUMO

Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.


Assuntos
Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia/tratamento farmacológico , Proteínas Mitocondriais/fisiologia , Mimetismo Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose , Humanos , Camundongos , Fator de Necrose Tumoral alfa/biossíntese
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