CREBBP Re-arrangements affect protein function and lead to aberrant neuronal differentiation

2010 ◽  
Vol 79 (4-5) ◽  
pp. 218-231 ◽  
Author(s):  
Neeti Sharma ◽  
Shweta P. Jadhav ◽  
Sharmila A. Bapat
Keyword(s):  
Neuronal Differentiation ◽  
Protein Function ◽  
Affect Protein Function

scholarly journals Single Amino Acid Polymorphisms of Pertussis Toxin Subunit S2 (PtxB) Affect Protein Function

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0137379 ◽  
Author(s):  
Scott H. Millen ◽  
Mineo Watanabe ◽  
Eiji Komatsu ◽  
Fuminori Yamaguchi ◽  
Yuki Nagasawa ◽  
...  
Keyword(s):  
Amino Acid ◽  
Pertussis Toxin ◽  
Protein Function ◽  
Single Amino Acid ◽  
Affect Protein Function ◽  
Single Amino Acid Polymorphisms

De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy

2018 ◽  
Vol 56 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Annalisa G Sega ◽  
Emily K Mis ◽  
Kristin Lindstrom ◽  
Saadet Mercimek-Andrews ◽  
Weizhen Ji ◽  
...  
Keyword(s):  
Genome Editing ◽  
Candidate Genes ◽  
Neuronal Differentiation ◽  
Protein Function ◽  
De Novo ◽  
Single Gene ◽  
Epileptic Encephalopathy ◽  
Epileptic Encephalopathies ◽  
Differentiation Factor

BackgroundEarly infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.ObjectivesThis study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative.MethodsWe used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles.ResultsWe identified novel de novo variants in neuronal differentiation factor 2 (NEUROD2) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients’ condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic.ConclusionThis study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.

The two AMD-associated variants of the factor H protein (V62I and Y402H) affect protein function and complement control

2008 ◽  
Vol 45 (16) ◽  
pp. 4116
Author(s):  
Nadine Lauer ◽  
Andrea Hartmann ◽  
Julia Böhme ◽  
Steffi Hälbich ◽  
Frank Sühnel ◽  
...  
Keyword(s):  
Protein Function ◽  
Factor H ◽  
Affect Protein Function ◽  
H Protein

scholarly journals SIFT: predicting amino acid changes that affect protein function

2003 ◽  
Vol 31 (13) ◽  
pp. 3812-3814 ◽  
Author(s):  
P. C. Ng
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Affect Protein Function

scholarly journals Accounting for Human Polymorphisms Predicted to Affect Protein Function

2002 ◽  
Vol 12 (3) ◽  
pp. 436-446 ◽  
Author(s):  
P. C. Ng
Keyword(s):  
Protein Function ◽  
Affect Protein Function

scholarly journals Akt Regulates Basic Helix-Loop-Helix Transcription Factor-Coactivator Complex Formation and Activity during Neuronal Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4417-4427 ◽  
Author(s):  
Anne B. Vojtek ◽  
Jennifer Taylor ◽  
Stacy L. DeRuiter ◽  
Jenn-Yah Yu ◽  
Claudia Figueroa ◽  
...  
Keyword(s):  
Growth Factors ◽  
Complex Formation ◽  
Neuronal Differentiation ◽  
Protein Function ◽  
Bhlh Protein ◽  
Akt Inhibitor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Peptide Growth Factors ◽  
Bhlh Proteins

ABSTRACT Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates. Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

scholarly journals Neurofibromatosis Type I Tumor Suppressor Neurofibromin Regulates Neuronal Differentiation via Its GTPase-activating Protein Function toward Ras

2003 ◽  
Vol 278 (29) ◽  
pp. 26958-26969 ◽  
Author(s):  
Shunji Yunoue ◽  
Hiroshi Tokuo ◽  
Kohji Fukunaga ◽  
Liping Feng ◽  
Tatsuya Ozawa ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Neuronal Differentiation ◽  
Protein Function ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Gtpase Activating Protein

scholarly journals Attenuated Expression of the mgaVirulence Regulon in an M Serotype 50 Mouse-Virulent Group A Streptococcal Strain

1999 ◽  
Vol 67 (12) ◽  
pp. 6691-6694 ◽  
Author(s):  
Der-Li Yung ◽  
Kevin S. McIver ◽  
June R. Scott ◽  
Susan K. Hollingshead
Keyword(s):  
Amino Acid ◽  
Gene Product ◽  
Protein Function ◽  
Virulence Genes ◽  
M Protein ◽  
Affect Protein Function ◽  
Group A ◽  
Virulent Group ◽  
Streptococcal Strain

ABSTRACT The attenuated expression of virulence genes found in a group A streptococcal strain that is naturally pathogenic for mice was postulated to result from a defect in the strain's multigene regulator, Mga. The sequence of the mga gene reveals three amino acid changes in the gene product that might affect protein function. The defect in the mga gene was complemented by providing either the closely similar mga4 allele or a more divergent mga1 allele in trans. Complementation increased the amount of emm50 transcript and the quantity of surface-extractable M protein, restoring virulence function.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

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