Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2014 Oct 31;28944:30578-30589. doi: 10.1074/jbc.M114.582221.
Show Gene links
Show Anatomy links
Identification of a point mutation impairing the binding between aquaporin-4 and neuromyelitis optica autoantibodies.
Pisani F
,
Mola MG
,
Simone L
,
Rosito S
,
Alberga D
,
Mangiatordi GF
,
Lattanzi G
,
Nicolotti O
,
Frigeri A
,
Svelto M
,
Nicchia GP
.
???displayArticle.abstract???
Neuromyelitis optica (NMO) is characterized by the presence of pathogenic autoantibodies (NMO-IgGs) against supra-molecular assemblies of aquaporin-4 (AQP4), known as orthogonal array of particles (OAPs). NMO-IgGs have a polyclonal origin and recognize different conformational epitopes involving extracellular AQP4 loops A, C, and E. Here we hypothesize a pivotal role for AQP4 transmembrane regions (TMs) in epitope assembly. On the basis of multialignment analysis, mutagenesis, NMO-IgG binding, and cytotoxicity assay, we have disclosed the key role of aspartate 69 (Asp(69)) of TM2 for NMO-IgG epitope assembly. Mutation of Asp(69) to histidine severely impairs NMO-IgG binding for 85.7% of the NMO patient sera analyzed here. Although Blue Native-PAGE, total internal reflection fluorescence microscopy, and water transport assays indicate that the OAP Asp(69) mutant is similar in structure and function to the wild type, molecular dynamic simulations have revealed that the D(69)H mutation has the effect of altering the structural rearrangements of extracellular loop A. In conclusion, Asp(69) is crucial for the spatial control of loop A, the particular molecular conformation of which enables the assembly of NMO-IgG epitopes. These findings provide additional clues for new strategies for NMO treatment and a wealth of information to better approach NMO pathogenesis.
Freedman,
Comparison of low-molecular-weight products following reaction of C3-C3b with C3b inactivator and with trypsin.
1977, Pubmed
Freedman,
Comparison of low-molecular-weight products following reaction of C3-C3b with C3b inactivator and with trypsin.
1977,
Pubmed
Hinson,
Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes.
2012,
Pubmed
Hinson,
Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica.
2007,
Pubmed
Ho,
Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance.
2009,
Pubmed
Hughes-Jones,
Activation of human complement by glutaraldehyde-treated red cells.
1977,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Iorio,
Astrocytic autoantibody of neuromyelitis optica (NMO-IgG) binds to aquaporin-4 extracellular loops, monomers, tetramers and high order arrays.
2013,
Pubmed
Jarius,
Revised diagnostic criteria for neuromyelitis optica--incorporation of NMO-IgG status.
2007,
Pubmed
Kalluri,
Quantification and functional characterization of antibodies to native aquaporin 4 in neuromyelitis optica.
2010,
Pubmed
Lennon,
IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
2005,
Pubmed
Lennon,
A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
,
Pubmed
MacKerell,
Development and current status of the CHARMM force field for nucleic acids.
,
Pubmed
Matiello,
Aquaporin 4 expression and tissue susceptibility to neuromyelitis optica.
2013,
Pubmed
Matiello,
Genetic analysis of aquaporin-4 in neuromyelitis optica.
2011,
Pubmed
Mola,
Automated cell-based assay for screening of aquaporin inhibitors.
2009,
Pubmed
Nelson,
Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica.
2010,
Pubmed
Nicchia,
Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex.
2008,
Pubmed
Nicchia,
D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness.
2011,
Pubmed
,
Xenbase
Nicchia,
Higher order structure of aquaporin-4.
2010,
Pubmed
Nicchia,
Dystrophin-dependent and -independent AQP4 pools are expressed in the mouse brain.
2008,
Pubmed
Nicchia,
Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies.
2009,
Pubmed
Nordlund,
Introduction of histidine residues into avidin subunit interfaces allows pH-dependent regulation of quaternary structure and biotin binding.
2003,
Pubmed
Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed
Phuan,
Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays.
2012,
Pubmed
Pisani,
Aquaporin-4 autoantibodies in Neuromyelitis Optica: AQP4 isoform-dependent sensitivity and specificity.
2013,
Pubmed
Pisani,
Identification of two major conformational aquaporin-4 epitopes for neuromyelitis optica autoantibody binding.
2011,
Pubmed
Pittock,
Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.
2013,
Pubmed
Polman,
Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
2011,
Pubmed
Ratelade,
Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss.
2012,
Pubmed
Ratelade,
Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
2012,
Pubmed
Rossi,
Post-Golgi supramolecular assembly of aquaporin-4 in orthogonal arrays.
2012,
Pubmed
Rossi,
Evidences for a leaky scanning mechanism for the synthesis of the shorter M23 protein isoform of aquaporin-4: implication in orthogonal array formation and neuromyelitis optica antibody interaction.
2010,
Pubmed
Schumaker,
A molecular mechanism for the activation of the first component of complement by immune complexes.
1986,
Pubmed
Sledge,
Binding properties of the human complement protein Clq.
1973,
Pubmed
Slotkin,
Adenosine-to-inosine RNA editing and human disease.
2013,
Pubmed
Verbavatz,
Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4.
1997,
Pubmed
Wingerchuk,
Revised diagnostic criteria for neuromyelitis optica.
2006,
Pubmed
