Compensatory Energetic Mechanisms Mediating the Assembly of Signaling Complexes Between Interleukin-2 and its α, β, and γc Receptors

Rickert, Mathias; Boulanger, Martin J.; Goriatcheva, Natalia; García, K. Christopher

doi:10.1016/j.jmb.2004.04.038

Cited by 74 publications

(60 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, the IL-2R␣͞IL-2 complex is likely to be preferentially delivered to IL-2R␤, forming the pseudo-high-affinity complex, in agreement with isothermal titration calorimetry experiments (28). This complex then recruits ␥ c , possibly from ␥ c trimers, burying a large surface area between the receptor subunits (Table 1) and forming a tight three-way junction comprising IL-2R␤, ␥ c , and IL-2.…”

Section: Figsupporting

confidence: 77%

“…7, which is published as supporting information on the PNAS web site). Such lateral interactions would lead to one-dimensional lattices of IL-2R complexes on the cell surface that could promote higher-order signaling assemblies, although no measurable affinity between soluble IL-2R␣ and ␥ c has been detected (28). However, this same set of experiments also did not detect any binding between IL-2R␤ and ␥ c , which in fact form an extensive interface in the fully assembled IL-2R.…”

Section: Interface Between Il-2r␣ and ␥C: Crystal Artifact Or Physiolmentioning

confidence: 81%

“…This receptor subunit, together with IL-2R␤, can form a pseudohigh-affinity site for IL-2 on the cell surface (K d Ϸ 300 pM), yet IL-2R␤ itself binds IL-2 only with modest affinity (K d Ϸ 450 nM) (31). In contrast, a soluble form of IL-2R␤ comprising solely its ectodomain exhibits comparable IL-2 affinity (K d Ϸ 144 nM) to its membrane-bound form, but only Ϸ2-fold increased affinity (K d Ϸ 64 nM) upon addition of soluble IL-2R␣ (28). Minor changes observed in the IL-2 structure in response to IL-2R␣ binding are probably sufficient to explain the 2-fold increase in IL-2R␤ affinity for IL-2 in solution.…”

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

Stauber

Debler

Horton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

234

217

View full text Add to dashboard Cite

IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R␣, IL-2R␤, and ␥c. Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 Å resolution. The quaternary structure is consistent with a stepwise assembly from IL-2͞IL-2R␣ to IL-2͞IL-2R␣͞IL-2R␤ to IL-2͞IL-2R␣͞IL-2R␤͞␥c. The IL-2R␣ subunit forms the largest of the three IL-2͞IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R␣ with IL-2 at the cell surface. Surprisingly, IL-2R␣ makes no contacts with IL-2R␤ or ␥c, and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R␣ to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R␤ and ␥c subunits. Helix A of IL-2 wedges tightly between IL-2R␤ and ␥c to form a three-way junction that coalesces into a composite binding site for the final ␥c recruitment. The IL-2͞␥c interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.common ␥ chain ͉ cooperativity ͉ IL-2 receptor ͉ receptor assembly ͉ structure-activity relationship

show abstract

Section: Figsupporting

confidence: 77%

Section: Interface Between Il-2r␣ and ␥C: Crystal Artifact Or Physiolmentioning

confidence: 81%

Section: Figmentioning

confidence: 99%

See 1 more Smart Citation

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

Stauber

Debler

Horton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

234

217

View full text Add to dashboard Cite

show abstract

“…30,31 É muito utilizada no estudo de processos por complexometria, tendo como fundamento a medida do fluxo de calor envolvido na reação. 32,33 Efetua-se uma titulação microcalorimétrica para medir a extensão da interação (ou ligação) de uma molécula (componente A) que é adicionada em quantidades e concentrações definidas a outra molécula (componente B), medindo-se o calor gerado.…”

Section: Titulação Calorimétrica Isotérmica (Itc)unclassified

Investigação eletroquímica e calorimétrica da interação de novos agentes antitumorais biscatiônicos com DNA

Silva¹,

Donnici²,

Lopes³

et al. 2012

Quím. Nova

View full text Add to dashboard Cite

Recebido em 12/7/11; aceito em 24/2/12; publicado na web em 15/6/12 ELECTROCHEMICAL AND CALORIMETRIC INVESTIGATION OF INTERACTION OF NOVEL BISCATIONIC ANTICANCER AGENTS WITH DNA. Biscationic amidines bind in the DNA minor groove and present biological activity against a range of infectious diseases. Two new biscationic compounds (bis-α,ω-S-thioureido, amino and sulfide analogues) were synthesized in good yields and fully characterized, and their interaction with DNA was also investigated. Isothermal titration calorimetry (ITC) was used to measure the thermodynamic properties of binding interactions between DNA and these ligands. A double stranded calf thymus DNA immobilized on an electrode surface was used to study the possible DNA-interacting abilities of these compounds towards dsDNA in situ. A remarkable interaction of these compounds with DNA was demonstrated and their potential application as anticancer agents was furthered.Keywords: biscationic compounds and interaction with DNA; isothermal titration calorimetry; electrochemical biosensor. INTRODUÇÃOO câncer é uma das doenças que mais causam temor na sociedade, por ter se tornado estigma de mortalidade e dor.1-3 Na verdade, a palavra câncer refere-se ao termo neoplasia, especificamente aos tumores malignos, doença caracterizada pelo crescimento descontrolado de células transformadas; 1 o termo câncer é utilizado genericamente para representar um conjunto de mais de 100 doenças.1,2 Na verdade, quase todos os organismos multicelulares podem ser afetados pelo câncer, inclusive lesões cancerosas foram encontradas em fósseis de dinossauros e em múmias do Egito Antigo. 4,5 Segundo a Organização Mundial da Saúde (OMS), o câncer é a segunda maior causa de mortalidade em todo mundo, atrás apenas das doenças de origem cardiovascular.6 Em 2008, a Agência Internacional para Pesquisa em Câncer (IARC/OMS) estimou que ocorreram 12,4 milhões de casos novos e 7,6 milhões de óbitos por câncer no mundo, e a OMS prevê que 84 milhões de pessoas devem morrer de câncer entre 2005 e 2015.7 Cerca de 1,5 milhão de casos de câncer são diagnosticados anualmente só nos EUA, e os médicos e pesquisadores do país estão engajados numa "guerra contra o câncer". 6,7 No Brasil, o câncer apresenta-se como a segunda maior causa de morte nos últimos anos; as estimativas do Instituto Nacional de Câncer (INCA) apontam que, até o final de 2008, ocorreram mais de 470 mil novos casos de câncer, número maior do que o de pessoas infectadas pelo vírus da AIDS nos últimos 25 anos, por exemplo. As estimativas para 2010 são válidas, também, para 2011 e apontam a ocorrência de 489.270 novos casos de câncer. Os tipos mais incidentes de câncer, à exceção do câncer de pele do tipo não melanoma, serão os de próstata e de pulmão, no sexo masculino, e os de mama e colo do útero, no sexo feminino. 1,8 Embora nenhum medicamento ou tratamento definitivo contra o câncer tenha ainda sido encontrado, tem-se obtido grande progresso na compreensão das causas do câncer, no desenvolvimento de tratamentos efetivos e de ...

show abstract

“…JAK activation, on the other hand, is essential for recruitment and phosphorylation of STAT proteins and PI-3 kinases which is a common pathway of all c cytokines [4] . Interestingly, while c is essential for c cytokine signaling, c itself does not show any specificity for a particular cytokine and c alone cannot bind free ligands [5] . Consequently, expression of cytokine specific receptor subunits, such as IL-7 receptor -chain (IL-7R) for IL-7 or IL-2R for IL-2, is deemed critical to confer ligand specificity and to initiate c receptor signaling.…”

Section: Introductionmentioning

confidence: 99%

The advent of soluble common gamma chain rocks the T cell world; A novel therapeutic target for autoimmune diseases

Lee¹,

Hong²

2014

Inflamm Cell Signal

View full text Add to dashboard Cite

The common gamma chain (γc) is the central signaling unit for the γc cytokine receptor family. γc cytokine signaling is mainly regulated by cytokine-specific receptor alpha chain expression levels but not γc expression levels. Here we will highlight that a soluble form of γc (sγc) expression, which is generated by alternative splicing, impairs naïve T cell survival and promotes inflammation in a manner of inhibiting IL-7 and IL-2 signaling, representatively. Furthermore, sγc expression is significantly enhanced upon T cell activation. sγc enhances in vitro and in vivo Th17 differentiation through dampening of IL-2 signal, and sγc-overexpressing mice are consequently more susceptible to EAE. Therefore, sγc is a novel immunoregulator that control T cell biology by regulation of γc cytokine signaling.

show abstract

Compensatory Energetic Mechanisms Mediating the Assembly of Signaling Complexes Between Interleukin-2 and its α, β, and γc Receptors

Cited by 74 publications

References 62 publications

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

Investigação eletroquímica e calorimétrica da interação de novos agentes antitumorais biscatiônicos com DNA

The advent of soluble common gamma chain rocks the T cell world; A novel therapeutic target for autoimmune diseases

Contact Info

Product

Resources

About