Kazuhiro Ogata - Academia.edu (original) (raw)

Papers by Kazuhiro Ogata

Research paper thumbnail of Structural basis of transcription regulation by CNC family transcription factor, Nrf2

Nucleic Acids Research

Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-bind... more Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of CNC family or the EHR motif of small Maf (sMaf) proteins. CNC family proteins heterodimerize with sMaf proteins to recognize CNC–sMaf binding DNA elements (CsMBEs) in competition with sMaf homodimers, but the functional role of the CNC motif remains elusive. In this study, we report the crystal structures of Nrf2/NFE2L2, a CNC family protein regulating anti-stress transcriptional responses, in a complex with MafG and CsMBE. The CNC motif restricts the conformations of crucial Arg residues in the basic region, which form extensive contact with the DNA backbone phosphates. Accordingly, the Nrf2–MafG heterodimer has approximately a 200-fold stronger affinity for CsMBE than canonical bZIP proteins, such as AP-1 proteins. The high DNA affinity of the CNC–sMaf heterodimer may allow it to compete with the sMaf homodimer on target genes without being perturb...

Research paper thumbnail of PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder

Journal of Human Genetics, 2017

Research paper thumbnail of Novel compound heterozygous LIAS mutations cause glycine encephalopathy

Journal of Human Genetics, 2015

Research paper thumbnail of A hemizygous GYG2 mutation and Leigh syndrome: a possible link?

Research paper thumbnail of Analysis on denatured state of c-Myb DNA-binding domain

Research paper thumbnail of Multi-state thermal transitions of proteins - DNA-binding domain of the c-Myb oncoprotein

Pure and Applied Chemistry, 1998

Research paper thumbnail of Recognition of specific DNA sequences by the c-myb protooncogene product: role of three repeat units in the DNA-binding domain

Proceedings of the National Academy of Sciences, 1993

The DNA-binding domain of c-Myb consists of three homologous tandem repeats of 52 amino acids. Th... more The DNA-binding domain of c-Myb consists of three homologous tandem repeats of 52 amino acids. The structure of the third (C-terminal) repeat obtained by NMR analysis has a conformation related to the helix-turn-helix motif. To identify the role of each repeat in the sequence recognition of DNA, we analyzed specific interactions between c-Myb and DNA by measuring binding affinities for systematic mutants of Myb-binding DNA sites and various truncated c-Myb mutants. We found that specific interactions are localized unevenly in the AACTGAC region in the consensus binding site of c-Myb: The first adenine, third cytosine, and fifth guanine are involved in very specific interactions, in which any base substitutions reduce the binding affinity by > 500-fold. On the other hand, the interaction at the second adenine is less specific, with the affinity reduction in the range of 6- to 15-fold. The seventh cytosine involves a rather peculiar interaction, in which only guanine substitution a...

Research paper thumbnail of Solution structure of a specific DNA complex of the Myb DNA-binding domain with cooperative recognition helices

Cell, 1994

with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:

Research paper thumbnail of Crystallization of the Ets1-Runx1-CBFβ-DNA complex formed on the TCRα gene enhancer

Acta crystallographica. Section F, Structural biology communications, 2014

Gene transcription is regulated in part through the assembly of multiple transcription factors (T... more Gene transcription is regulated in part through the assembly of multiple transcription factors (TFs) on gene enhancers. To enable examination of the mechanism underlying the formation of these complexes and their response to a phosphorylation signal, two kinds of higher-order TF-DNA assemblies were crystallized composed of an unmodified or phosphorylated Ets1 fragment, a Runx1(L94K) fragment and a CBFβ fragment on the T-cell receptor (TCR) α gene enhancer. Within these complexes, the Ets1 and Runx1 fragments contain intrinsically disordered regulatory regions as well as their DNA-binding domains. Crystals of the complex containing unmodified Ets1 belonged to space group P212121, with unit-cell parameters a = 78.7, b = 102.1, c = 195.0 Å, and diffracted X-rays to a resolution of 2.35 Å, and those containing phosphorylated Ets1 belonged to the same space group, with unit-cell parameters a = 78.6, b = 101.7, c = 194.7 Å, and diffracted X-rays to a similar resolution. To facilitate crys...

Research paper thumbnail of Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Journal of Human Genetics, 2012

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial... more Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T4C (p.Leu60Pro) mutation occurred de novo and the c.362G4C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Research paper thumbnail of Mitochondrial Complex III Deficiency Caused by a Homozygous UQCRC2 Mutation Presenting with Neonatal-Onset Recurrent Metabolic Decompensation

Human Mutation, 2013

Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and g... more Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive. Here, we report three patients from a consanguineous Mexican family presenting with neonatal onset of hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. We found a homozygous missense mutation in UQCRC2 that encodes mitochondrial ubiquinol-cytochrome c reductase core protein II by whole-exome sequencing combined with linkage analysis. On the basis of structural modeling, the mutation (p.Arg183Trp) was predicted to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer. In vitro studies using fibroblasts from the index patient clearly indicated CIII deficiency, as well as impaired assembly of the supercomplex formed from complexes I, III, and IV. This is the

Research paper thumbnail of Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy

The American Journal of Human Genetics, 2013

Research paper thumbnail of Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy

The American Journal of Human Genetics, 2011

Research paper thumbnail of Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy

The American Journal of Human Genetics, 2013

Research paper thumbnail of Dominant-Negative Mutations in α-II Spectrin Cause West Syndrome with Severe Cerebral Hypomyelination, Spastic Quadriplegia, and Developmental Delay

The American Journal of Human Genetics, 2010

Research paper thumbnail of Structural basis of the regulation of normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2

SummaryDimethylated histone H3 Lys36 (H3K36me2) regulates gene expression by antagonizing the rep... more SummaryDimethylated histone H3 Lys36 (H3K36me2) regulates gene expression by antagonizing the repressive effect of polycomb-group proteins. Aberrant upregulation of H3K36me2, either by overexpression or point mutations of NSD2/MMSET, an H3K36 dimethyltransferase, is found in various cancers, including multiple myeloma. To understand the mechanism underlying its regulation, here we report the cryo-electron microscopy structure of the catalytic fragment of NSD2 bound to the nucleosome at 2.8 Å resolution. The nucleosomal DNA is partially unwrapped at superhelix location +5.5, facilitating the access of NSD2 to H3K36. NSD2 interacts with DNA and H2A along with H3. The autoinhibitory loop of NSD2 changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed two oncogenic mutations, E1099K and T1150A, to aberrantly activate NSD2 by increasing its catalytic turnover but not the nucleosome affinity. Molecular dynamics simulatio...

Research paper thumbnail of Structural analysis of the Nrf 2-containing enhanceosome that regulates oxidative stress responsive genes

Research paper thumbnail of X-ray crystallographic analysis of Runx1-CBF-Ets1-DNA complex assembled on the enhancer of T cell receptor chain gene

Introduction Target gene specificity in transcriptional regulation is determined by an enhanceoso... more Introduction Target gene specificity in transcriptional regulation is determined by an enhanceosome comprised of a distinct set of multiple transcription factors formed on a ciselement in an enhancer region. An enhanceosome is assumed to respond dynamically to various cell signals through chemical modifications, such as phosphorylation, of transcription factors. Phosphorylation of transcription factors is reported to control transactivation of target genes. However, the role of phosphorylation of transcription factors in the context of an enhanceosome on a target gene enhancer remains unclear. To reveal the underlying mechanism, we focused on the Ets1–Runx1– CBF–DNA complex, the most important part of the enhanceosome formed on the TCRenhancer. Ets1 activity is negatively regulated by the regulatory region (the exon VII) flanking its DNA binding domain (so called the ETS domain) and phosphorylations of the exon VII suppress more strongly DNA binding activity of Ets1. Runx1, which...

Research paper thumbnail of Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2

Nature Communications

Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregul... more Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide t...

Research paper thumbnail of A novel GFI1B mutation at the first zinc finger domain causes congenital macrothrombocytopenia

British journal of haematology, Jan 25, 2017

Research paper thumbnail of Structural basis of transcription regulation by CNC family transcription factor, Nrf2

Nucleic Acids Research

Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-bind... more Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of CNC family or the EHR motif of small Maf (sMaf) proteins. CNC family proteins heterodimerize with sMaf proteins to recognize CNC–sMaf binding DNA elements (CsMBEs) in competition with sMaf homodimers, but the functional role of the CNC motif remains elusive. In this study, we report the crystal structures of Nrf2/NFE2L2, a CNC family protein regulating anti-stress transcriptional responses, in a complex with MafG and CsMBE. The CNC motif restricts the conformations of crucial Arg residues in the basic region, which form extensive contact with the DNA backbone phosphates. Accordingly, the Nrf2–MafG heterodimer has approximately a 200-fold stronger affinity for CsMBE than canonical bZIP proteins, such as AP-1 proteins. The high DNA affinity of the CNC–sMaf heterodimer may allow it to compete with the sMaf homodimer on target genes without being perturb...

Research paper thumbnail of PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder

Journal of Human Genetics, 2017

Research paper thumbnail of Novel compound heterozygous LIAS mutations cause glycine encephalopathy

Journal of Human Genetics, 2015

Research paper thumbnail of A hemizygous GYG2 mutation and Leigh syndrome: a possible link?

Research paper thumbnail of Analysis on denatured state of c-Myb DNA-binding domain

Research paper thumbnail of Multi-state thermal transitions of proteins - DNA-binding domain of the c-Myb oncoprotein

Pure and Applied Chemistry, 1998

Research paper thumbnail of Recognition of specific DNA sequences by the c-myb protooncogene product: role of three repeat units in the DNA-binding domain

Proceedings of the National Academy of Sciences, 1993

The DNA-binding domain of c-Myb consists of three homologous tandem repeats of 52 amino acids. Th... more The DNA-binding domain of c-Myb consists of three homologous tandem repeats of 52 amino acids. The structure of the third (C-terminal) repeat obtained by NMR analysis has a conformation related to the helix-turn-helix motif. To identify the role of each repeat in the sequence recognition of DNA, we analyzed specific interactions between c-Myb and DNA by measuring binding affinities for systematic mutants of Myb-binding DNA sites and various truncated c-Myb mutants. We found that specific interactions are localized unevenly in the AACTGAC region in the consensus binding site of c-Myb: The first adenine, third cytosine, and fifth guanine are involved in very specific interactions, in which any base substitutions reduce the binding affinity by > 500-fold. On the other hand, the interaction at the second adenine is less specific, with the affinity reduction in the range of 6- to 15-fold. The seventh cytosine involves a rather peculiar interaction, in which only guanine substitution a...

Research paper thumbnail of Solution structure of a specific DNA complex of the Myb DNA-binding domain with cooperative recognition helices

Cell, 1994

with specic help available everywhere you see the i O symbol. The following versions of software ... more with specic help available everywhere you see the i O symbol. The following versions of software and data (see references i O) were used in the production of this report:

Research paper thumbnail of Crystallization of the Ets1-Runx1-CBFβ-DNA complex formed on the TCRα gene enhancer

Acta crystallographica. Section F, Structural biology communications, 2014

Gene transcription is regulated in part through the assembly of multiple transcription factors (T... more Gene transcription is regulated in part through the assembly of multiple transcription factors (TFs) on gene enhancers. To enable examination of the mechanism underlying the formation of these complexes and their response to a phosphorylation signal, two kinds of higher-order TF-DNA assemblies were crystallized composed of an unmodified or phosphorylated Ets1 fragment, a Runx1(L94K) fragment and a CBFβ fragment on the T-cell receptor (TCR) α gene enhancer. Within these complexes, the Ets1 and Runx1 fragments contain intrinsically disordered regulatory regions as well as their DNA-binding domains. Crystals of the complex containing unmodified Ets1 belonged to space group P212121, with unit-cell parameters a = 78.7, b = 102.1, c = 195.0 Å, and diffracted X-rays to a resolution of 2.35 Å, and those containing phosphorylated Ets1 belonged to the same space group, with unit-cell parameters a = 78.6, b = 101.7, c = 194.7 Å, and diffracted X-rays to a similar resolution. To facilitate crys...

Research paper thumbnail of Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Journal of Human Genetics, 2012

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial... more Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T4C (p.Leu60Pro) mutation occurred de novo and the c.362G4C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Research paper thumbnail of Mitochondrial Complex III Deficiency Caused by a Homozygous UQCRC2 Mutation Presenting with Neonatal-Onset Recurrent Metabolic Decompensation

Human Mutation, 2013

Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and g... more Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive. Here, we report three patients from a consanguineous Mexican family presenting with neonatal onset of hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. We found a homozygous missense mutation in UQCRC2 that encodes mitochondrial ubiquinol-cytochrome c reductase core protein II by whole-exome sequencing combined with linkage analysis. On the basis of structural modeling, the mutation (p.Arg183Trp) was predicted to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer. In vitro studies using fibroblasts from the index patient clearly indicated CIII deficiency, as well as impaired assembly of the supercomplex formed from complexes I, III, and IV. This is the

Research paper thumbnail of Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy

The American Journal of Human Genetics, 2013

Research paper thumbnail of Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy

The American Journal of Human Genetics, 2011

Research paper thumbnail of Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy

The American Journal of Human Genetics, 2013

Research paper thumbnail of Dominant-Negative Mutations in α-II Spectrin Cause West Syndrome with Severe Cerebral Hypomyelination, Spastic Quadriplegia, and Developmental Delay

The American Journal of Human Genetics, 2010

Research paper thumbnail of Structural basis of the regulation of normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2

SummaryDimethylated histone H3 Lys36 (H3K36me2) regulates gene expression by antagonizing the rep... more SummaryDimethylated histone H3 Lys36 (H3K36me2) regulates gene expression by antagonizing the repressive effect of polycomb-group proteins. Aberrant upregulation of H3K36me2, either by overexpression or point mutations of NSD2/MMSET, an H3K36 dimethyltransferase, is found in various cancers, including multiple myeloma. To understand the mechanism underlying its regulation, here we report the cryo-electron microscopy structure of the catalytic fragment of NSD2 bound to the nucleosome at 2.8 Å resolution. The nucleosomal DNA is partially unwrapped at superhelix location +5.5, facilitating the access of NSD2 to H3K36. NSD2 interacts with DNA and H2A along with H3. The autoinhibitory loop of NSD2 changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed two oncogenic mutations, E1099K and T1150A, to aberrantly activate NSD2 by increasing its catalytic turnover but not the nucleosome affinity. Molecular dynamics simulatio...

Research paper thumbnail of Structural analysis of the Nrf 2-containing enhanceosome that regulates oxidative stress responsive genes

Research paper thumbnail of X-ray crystallographic analysis of Runx1-CBF-Ets1-DNA complex assembled on the enhancer of T cell receptor chain gene

Introduction Target gene specificity in transcriptional regulation is determined by an enhanceoso... more Introduction Target gene specificity in transcriptional regulation is determined by an enhanceosome comprised of a distinct set of multiple transcription factors formed on a ciselement in an enhancer region. An enhanceosome is assumed to respond dynamically to various cell signals through chemical modifications, such as phosphorylation, of transcription factors. Phosphorylation of transcription factors is reported to control transactivation of target genes. However, the role of phosphorylation of transcription factors in the context of an enhanceosome on a target gene enhancer remains unclear. To reveal the underlying mechanism, we focused on the Ets1–Runx1– CBF–DNA complex, the most important part of the enhanceosome formed on the TCRenhancer. Ets1 activity is negatively regulated by the regulatory region (the exon VII) flanking its DNA binding domain (so called the ETS domain) and phosphorylations of the exon VII suppress more strongly DNA binding activity of Ets1. Runx1, which...

Research paper thumbnail of Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2

Nature Communications

Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregul... more Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide t...

Research paper thumbnail of A novel GFI1B mutation at the first zinc finger domain causes congenital macrothrombocytopenia

British journal of haematology, Jan 25, 2017