| dc.contributor.author |
Douni, E |
en |
| dc.contributor.author |
Rinotas, V |
en |
| dc.contributor.author |
Makrinou, E |
en |
| dc.contributor.author |
Zwerina, J |
en |
| dc.contributor.author |
Penninger, JM |
en |
| dc.contributor.author |
Eliopoulos, E |
en |
| dc.contributor.author |
Schett, G |
en |
| dc.contributor.author |
Kollias, G |
en |
| dc.date.accessioned |
2014-06-06T06:51:35Z |
|
| dc.date.available |
2014-06-06T06:51:35Z |
|
| dc.date.issued |
2012 |
en |
| dc.identifier.issn |
09646906 |
en |
| dc.identifier.uri |
http://dx.doi.org/10.1093/hmg/ddr510 |
en |
| dc.identifier.uri |
http://62.217.125.90/xmlui/handle/123456789/5584 |
|
| dc.subject.other |
arginine |
en |
| dc.subject.other |
glutathione transferase |
en |
| dc.subject.other |
glycine |
en |
| dc.subject.other |
monomer |
en |
| dc.subject.other |
osteoclast differentiation factor |
en |
| dc.subject.other |
receptor activator of nuclear factor kappa B |
en |
| dc.subject.other |
recombinant osteoclast differentiation factor |
en |
| dc.subject.other |
recombinant protein |
en |
| dc.subject.other |
tumor necrosis factor |
en |
| dc.subject.other |
unclassified drug |
en |
| dc.subject.other |
animal cell |
en |
| dc.subject.other |
animal experiment |
en |
| dc.subject.other |
animal model |
en |
| dc.subject.other |
animal tissue |
en |
| dc.subject.other |
article |
en |
| dc.subject.other |
autosomal recessive disorder |
en |
| dc.subject.other |
autosomal recessive osteopetrosis |
en |
| dc.subject.other |
codon |
en |
| dc.subject.other |
controlled study |
en |
| dc.subject.other |
crystal structure |
en |
| dc.subject.other |
ex vivo study |
en |
| dc.subject.other |
female |
en |
| dc.subject.other |
histopathology |
en |
| dc.subject.other |
human |
en |
| dc.subject.other |
human cell |
en |
| dc.subject.other |
hydrophobicity |
en |
| dc.subject.other |
in vitro study |
en |
| dc.subject.other |
in vivo study |
en |
| dc.subject.other |
loss of function mutation |
en |
| dc.subject.other |
male |
en |
| dc.subject.other |
missense mutation |
en |
| dc.subject.other |
mouse |
en |
| dc.subject.other |
nonhuman |
en |
| dc.subject.other |
nucleotide sequence |
en |
| dc.subject.other |
osteoclast |
en |
| dc.subject.other |
osteoclastogenesis |
en |
| dc.subject.other |
osteoporosis |
en |
| dc.subject.other |
priority journal |
en |
| dc.subject.other |
protein function |
en |
| dc.subject.other |
protein protein interaction |
en |
| dc.subject.other |
receptor binding |
en |
| dc.subject.other |
wild type |
en |
| dc.subject.other |
Amino Acid Substitution |
en |
| dc.subject.other |
Animals |
en |
| dc.subject.other |
Disease Models, Animal |
en |
| dc.subject.other |
Ethylnitrosourea |
en |
| dc.subject.other |
Genes, Dominant |
en |
| dc.subject.other |
Mice |
en |
| dc.subject.other |
Mutation, Missense |
en |
| dc.subject.other |
Osteoclasts |
en |
| dc.subject.other |
Osteopetrosis |
en |
| dc.subject.other |
Point Mutation |
en |
| dc.subject.other |
Protein Binding |
en |
| dc.subject.other |
Protein Multimerization |
en |
| dc.subject.other |
RANK Ligand |
en |
| dc.subject.other |
Receptor Activator of Nuclear Factor-kappa B |
en |
| dc.subject.other |
Tumor Necrosis Factor-alpha |
en |
| dc.subject.other |
Mus |
en |
| dc.title |
A RANKL G278R mutation causing osteopetrosis identifies a functional amino acid essential for trimer assembly in RANKL and TNF |
en |
| heal.type |
journalArticle |
en |
| heal.identifier.primary |
10.1093/hmg/ddr510 |
en |
| heal.identifier.secondary |
ddr510 |
en |
| heal.publicationDate |
2012 |
en |
| heal.abstract |
Receptor activator of nuclear factor-κB ligand (RANKL), a trimeric tumor necrosis factor (TNF) superfamily member, is the central mediator of osteoclast formation and bone resorption. Functional mutations in RANKL lead to human autosomal recessive osteopetrosis (ARO), whereas RANKL overexpression has been implicated in the pathogenesis of bone degenerative diseases such as osteoporosis. Following a forward genetics approach using N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we generated a novel mouse model of ARO caused by a new loss-of-function allele of Rankl with a glycine-to-arginine mutation at codon 278 (G278R) at the extracellular inner hydrophobic F β-strand of RANKL. Mutant mice develop severe osteopetrosis similar to Rankl-deficient mice, whereas exogenous administration of recombinant RANKL restores osteoclast formation in vivo. We show that RANKL G278R monomers fail to assemble into homotrimers, are unable to bind and activate the RANK receptor and interact with wild-type RANKL exerting a dominant-negative effect on its trimerization and function in vitro. Since G278 is highly conserved within the TNF superfamily, we identified that a similar substitution in TNF, G122R, also abrogated trimerization, binding to TNF receptor and consequently impaired TNF biological activity. Notably, SPD304, a potent small-molecule inhibitor of TNF trimerization that interacts with G122, also inhibited RANKL activity, suggesting analogous inhibitory mechanisms. Our results provide a new disease model for ARO and identify a functional amino acid in the TNF-like core domain essential for trimer formation both in RANKL and in TNF that could be considered a novel potential target for inhibiting their biological activities. © The Author 2011. Published by Oxford University Press. All rights reserved. |
en |
| heal.journalName |
Human Molecular Genetics |
en |
| dc.identifier.issue |
4 |
en |
| dc.identifier.volume |
21 |
en |
| dc.identifier.doi |
10.1093/hmg/ddr510 |
en |
| dc.identifier.spage |
784 |
en |
| dc.identifier.epage |
798 |
en |