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1.
Sci Rep ; 10(1): 13686, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792564

RESUMO

The neurotrophin receptor p75NTR plays crucial roles in neuron development and regulates important neuronal processes like degeneration, apoptosis and cell survival. At the same time the detailed mechanism of signal transduction is unclear. One of the main hypotheses known as the snail-tong mechanism assumes that in the inactive state, the death domains interact with each other and in response to ligand binding there is a conformational change leading to their exposure. Here, we show that neither rat nor human p75NTR death domains homodimerize in solution. Moreover, there is no interaction between the death domains in a more native context: the dimerization of transmembrane domains in liposomes and the presence of activating mutation in extracellular juxtamembrane region do not lead to intracellular domain interaction. These findings suggest that the activation mechanism of p75NTR should be revised. Thus, we propose a novel model of p75NTR functioning based on interaction with "helper" protein.


Assuntos
Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Receptores de Fatores de Crescimento/química , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fator de Crescimento Neural/química , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Humanos , Ligantes , Lipossomos/metabolismo , Modelos Moleculares , Proteínas do Tecido Nervoso/genética , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Multimerização Proteica , Ratos , Receptores de Fatores de Crescimento/genética , Receptores de Fator de Crescimento Neural/genética
2.
PLoS One ; 13(10): e0206244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30352081

RESUMO

RIP2, one of the RIP kinases, interacts with p75 neurotrophin receptor, regulating the neuron survival, and with NOD1 and NOD2 proteins, causing the innate immune response against gram-negative and gram-positive bacteria via its caspase recruitment domain (CARD). This makes RIP2 a prospective target for novel therapies, aimed to modulate the inflammatory diseases and neurogenesis/neurodegeneration. Several studies report the problems with the stability of human RIP2 CARD and its production in bacterial hosts, which is a prerequisite for the structural investigation with solution NMR spectroscopy. In the present work, we report the high yield production and refolding protocols and resolve the structure of rat RIP2 CARD. The structure reveals the important differences to the previously published conformation of the homologous human protein. Using solution NMR, we characterized the intramolecular mobility and pH-dependent behavior of RIP2 CARD, and found the propensity of the protein to form high-order oligomers at physiological pH while being monomeric under acidic conditions. The oligomerization of protein may be explained, based on the electrostatic properties of its surface. Analysis of the structure and sequences of homologous proteins reveals the residues which are significant for the unusual fold of RIP2 CARD domains from different species. The high-throughput protein production/refolding protocols and proposed explanation for the protein oligomerization, provide an opportunity to design the stabilized variants of RIP2 CARD, which could be used to study the structural details of RIP2/NOD1/NOD2 interaction and perform the rational drug design.


Assuntos
Domínio de Ativação e Recrutamento de Caspases , Multimerização Proteica , Redobramento de Proteína , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Sequência de Aminoácidos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Proteína Adaptadora de Sinalização NOD1/química , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/química , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Ligação Proteica , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Homologia de Sequência de Aminoácidos , Soluções , Eletricidade Estática
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