A5055281025- RNA Research and Splicing
- Cancer-related Molecular Pathways
- Protein Structure and Dynamics
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Heat shock proteins research
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Hippo pathway signaling and YAP/TAZ
- DNA and Nucleic Acid Chemistry
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- Bacterial Genetics and Biotechnology
- Genetics and Neurodevelopmental Disorders
- Bacterial biofilms and quorum sensing
- Radiopharmaceutical Chemistry and Applications
- Redox biology and oxidative stress
- RNA Interference and Gene Delivery
Scripps Research Institute
2012-2023
Scripps Institution of Oceanography
2022
Institute of Molecular Biology
2012
National Institute of Advanced Industrial Science and Technology
2009
University of Copenhagen
2008
Stockholm University
2008
Stanford University
1994-1996
The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates of critical adaptive genes recruitment general coactivators CBP/p300 through interactions with its α-subunit (Hif-1α). Disruption Hif-1α/p300 interaction has been linked attenuation tumor growth. To delineate structural basis for this interaction, we have determined solution structure complex between carboxy-terminal activation...
The tumor suppressor activity of p53 is regulated by interactions with the ubiquitin ligase HDM2 and general transcriptional coactivators CBP p300. Using NMR spectroscopy isothermal titration calorimetry, we have dissected binding between N-terminal transactivation domain (TAD) p53, TAZ1, TAZ2, KIX, nuclear receptor coactivator domains CBP, p53-binding HDM2. TAD contains amphipathic motifs within AD1 AD2 regions that mediate Binding to dominated AD2, although affinity enhanced additional...
The activity and stability of the tumor suppressor p53 are regulated by interactions with key cellular proteins such as MDM2 CBP/p300. transactivation domain (TAD) contains two subdomains (AD1 AD2) interacts directly N-terminal several domains Here we report NMR structure full-length TAD in complex nuclear coactivator binding (NCBD) CBP. Both NCBD intrinsically disordered fold synergistically upon binding, evidenced observed increase helicity increased level dispersion amide proton...
The adenovirus early region 1A (E1A) oncoprotein mediates cell transformation by deregulating host cellular processes and activating viral gene expression recruitment of proteins that include cyclic-AMP response element binding (CREB) protein (CBP)/p300 the retinoblastoma (pRb). While E1A is capable independent interaction with CBP/p300 or pRb, simultaneous both required for maximal biological activity. To obtain insights into mechanism which hijacks transcription machinery competing...
Methylation of CpG dinucleotides in DNA is a common epigenetic modification eukaryotes that plays central role maintenance genome stability, gene silencing, genomic imprinting, development, and disease. Kaiso, bifunctional Cys 2 His zinc finger protein implicated tumor-cell proliferation, binds to both methylated (mCpG) sites specific nonmethylated motif (TCCTGCNA) represses transcription by recruiting chromatin remodeling corepression machinery target genes. Here we report structures the...
Significance The tumor suppressor p53 regulates the cellular response to genomic damage by recruiting transcriptional coactivator cyclic-AMP element-binding protein (CREB)-binding (CBP) and its paralog p300 activate stress genes. We report NMR structures of complexes formed between full-length, intrinsically disordered N-terminal transactivation domain adapter zinc finger domains (TAZ1 TAZ2) CBP. Exchange broadening spectra was ameliorated using fusion proteins segmental isotope labeling....
Molecular interactions between the tumor suppressor p53 and transcriptional coactivators CBP/p300 are critical for regulation of transactivation stability. The domain (TAD) binds directly to several domains (TAZ1, TAZ2, NCBD, KIX). Here we map interaction TAD CBP KIX using isothermal titration calorimetry NMR spectroscopy. is a structural in that can simultaneously bind two polypeptide ligands, such as activation MLL kinase-inducible (pKID) CREB, distinct surfaces. consists subdomains (AD1...
Significance CREB-binding protein (CBP) and its paralog p300 play a vital role in regulating gene transcription. Through the enzymatic activity of their histone acetyltransferase (HAT) domain, CBP control accessibility genes chromatin activate They also function as transcriptional repressors following SUMOylation cell cycle regulatory domain 1 (CRD1) located N-terminal to catalytic core. We present structural biochemical results showing that bromodomain, CH2, ZZ domains, which flank regulate...
The molecular chaperone Hsp33 in Escherichia coli responds to oxidative stress conditions with the rapid activation of its function. On pathway, progresses through three major conformations, starting as a reduced, zinc-bound inactive monomer, proceeding an oxidized zinc-free and ending fully active dimer. While it is known that senses C-terminal four-cysteine zinc center, nature conformational changes must take place accommodate this process largely unknown. To investigate these...
The TAZ1 domain of the homologous transcriptional coactivators CREB-binding protein (CBP) and p300 forms a complex with CITED2 (CBP/p300-interacting transactivator ED-rich tail), inhibiting activity hypoxia inducible factor (HIF-1α) thereby attenuating cellular response to low tissue oxygen concentration. We report NMR structure CBP bound activation CIT-ED2. TAZ1, consisting four α-helices (α1-α4) stabilized by three zinc atoms, is very similar in HIF-1α complexes. unstructured when free...
Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This "knob" is analogous to natural cysteine-rich peptides such as knottins in that it small and stable but can accommodate diverse loops disulfide bonding patterns. We immunized cattle SARS-CoV-2 spike found CDR H3 could neutralize several viral variants at picomolar IC
The transcriptional coactivator protein CBP and its paralog p300 each contain two homologous zinc-containing TAZ domains, which constitute the interaction sites for a number of transcription factors. Previous reports three-dimensional structures TAZ1 in complex with binding partners isolated TAZ2 domain show distinctive topology composed four amphipathic helices, organized by three zinc-binding clusters HCCC-type coordination. forms stable structure solution, but recent report [Dial, R.,...