A5067633818- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Lysosomal Storage Disorders Research
- Enzyme Production and Characterization
- Enzyme Catalysis and Immobilization
- Alkaline Phosphatase Research Studies
- Biochemical and Molecular Research
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Organophosphorus compounds synthesis
- Opioid Use Disorder Treatment
- DNA Repair Mechanisms
- Neurological and metabolic disorders
- Ubiquitin and proteasome pathways
- Quantum, superfluid, helium dynamics
- Substance Abuse Treatment and Outcomes
- Pediatric Hepatobiliary Diseases and Treatments
- Microbial Metabolic Engineering and Bioproduction
- NMR spectroscopy and applications
- MicroRNA in disease regulation
- Pain Management and Placebo Effect
- RNA regulation and disease
- Advanced NMR Techniques and Applications
- Pancreatitis Pathology and Treatment
ETH Zurich
2016-2024
Institut Gustave Roussy
2021
University of Cambridge
2008-2018
Max Planck Institute for Developmental Biology
2010-2016
Délégation Paris 5
2016
Sorbonne Paris Cité
2016
Université Paris Cité
2016
Max Planck Society
2013-2014
Humboldt-Universität zu Berlin
1995-2008
Park Terrace Care Center
2007
Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control mechanism that detects aberrant mRNAs containing nonsense codons and induces their rapid degradation. This degradation mediated by SMG6, an NMD-specific endonuclease, as well the SMG5 SMG7 proteins, which recruit general enzymes. However, it remains unknown specific factors are recruited whether this recruitment direct. Here, we show binds directly to POP2, catalytic subunit of CCR4–NOT deadenylase complex, elicits...
The removal of the 5′-cap structure by decapping enzyme DCP2 and its coactivator DCP1 shuts down translation exposes mRNA to 5′-to-3′ exonucleolytic degradation XRN1. Although yeast directly interact, an additional factor, EDC4, promotes DCP1–DCP2 association in metazoan. Here, we elucidate how human proteins interact assemble active complex decapped mRNAs are handed over We show that EDC4 serves as a scaffold for assembly, providing binding sites DCP1, XRN1 bind simultaneously C-terminal...
The RNA-binding proteins of the Nanos family play an essential role in germ cell development and survival a wide range metazoan species. They function by suppressing expression target mRNAs through recruitment effector complexes, which include CCR4–NOT deadenylase complex. Here, we show that three human paralogs (Nanos1–3) interact with CNOT1 C-terminal domain determine structural basis for specific molecular recognition. Nanos1–3 bind short CNOT1-interacting motif (NIM) is conserved all...
RNA helicases of the DEAH/RHA family are involved in many essential cellular processes, such as splicing or ribosome biogenesis, where they remodel large RNA-protein complexes to facilitate transitions next intermediate. DEAH couple adenosine triphosphate (ATP) hydrolysis conformational changes their catalytic core. This movement results translocation along RNA, which is held place by auxiliary C-terminal domains. The activity proteins strongly enhanced and diverse class G-patch activators....
Progress in NMR general and biomolecular applications particular is driven by increasing magnetic-field strengths leading to improved resolution sensitivity of the spectra. Recently, persistent superconducting magnets at a magnetic field strength (magnetic induction) 28.2 T corresponding 1200 MHz proton resonance frequency became commercially available. We present here collection high-field spectra variety proteins, including molecular machines, membrane viral capsids, fibrils large...
The Integrator complex attenuates gene expression via the premature termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. It is required for stimulus response, cell differentiation, and neurodevelopment, but how gene-specific adaptive regulation by achieved remains unclear. Here, we identify two sites on human subunits 13/14 that serve as binding hubs sequence-specific transcription factors (TFs) other effector complexes. When attached to paused RNAP2, these are...
We report a catalytically promiscuous enzyme able to efficiently promote the hydrolysis of six different substrate classes. Originally assigned as phosphonate monoester hydrolase (PMH) this exhibits substantial second-order rate accelerations (( k cat / K M )/ w ), ranging from 10 7 high 19 , for hydrolyses phosphate mono-, di-, and triesters, monoesters, sulfate sulfonate monoesters. This collection encompasses range charges between 0 -2, transition states nature, involves attack at two...
The nonsense-mediated mRNA decay (NMD) pathway triggers the rapid degradation of aberrant mRNAs containing premature translation termination codons (PTCs). In metazoans, NMD requires three 14-3-3-like proteins: SMG5, SMG6, and SMG7. These proteins are recruited to PTC-containing through interaction their domains with phosphorylated UPF1, central effector. Recruitment SMG7 causes target degradation. this study, we report crystal structure Caenorhabditis elegans SMG5–SMG7 complex....
Abstract The Integrator complex processes 3′-ends of spliceosomal small nuclear RNAs (snRNAs). Furthermore, it regulates transcription protein coding genes by terminating after unstable pausing. molecular basis for Integrator’s functions remains obscure. Here, we show that INTS10, Asunder/INTS13 and INTS14 form a separable, functional module. structure INTS13-INTS14 reveals strongly entwined with unique chain interlink. Unexpected structural homology to the Ku70-Ku80 DNA repair suggests...
Significance Pre-messenger RNA (pre-mRNA) splicing is a key regulatory step in gene expression. The reaction mediated by the spliceosome, dynamic complex comprising five small nuclear ribonucleoproteins (snRNPs), which assembles onto each intron multiple steps. We present detailed structural analysis and supporting functional data of an important protein–RNA interaction between human U1 U2 snRNP. Our structure shows that intrinsically disordered arginine-glycine (RGG/RG)–rich motif snRNP...
Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and degrades mRNAs containing premature stop codons (PTCs). In vertebrates, PTCs trigger efficient NMD when located upstream of an exon junction complex (EJC). Degradation PTC-containing requires the endonucleolytic activity SMG6, conserved factor; nevertheless, precise role for EJC in how SMG6 endonuclease recruited to targets have been unclear. Here we show interacts directly with via two EJC-binding motifs...
Establishment of translational competence represents a decisive cytoplasmic step in the biogenesis 40S ribosomal subunits. This involves final 18S rRNA processing and release residual factors, including protein kinase RIOK1. To identify novel proteins promoting maturation human subunits, we characterized pre-ribosomal subunits trapped on RIOK1 by mass spectrometry, identified deubiquitinase USP16 among captured factors. We demonstrate that constitutes component late pre-40S promotes removal...
Abstract "Promiscuous" enzymes possess activities in addition to their native ones. Promiscuous could be remnants from an evolutionary ancestor that has been adapted fulfil a new function following gene duplication. Alternatively, the observation of promiscuity indicate enzyme potential evolve into catalyst. Thus, defines functional relationships superfamilies. Crosswise can provide additional layer connectivity between members - usually structurally defined superfamily establish system for...
Highly proficient, promiscuous enzymes can be springboards for functional evolution, able to avoid loss of function during adaptation by their capacity promote multiple reactions. We employ a systematic comparative study structure, sequence, and substrate specificity track the evolution reactivity between members clades alkaline phosphatase (AP) superfamily. Construction phylogenetic tree protein sequences maps out likely transition zone arylsulfatases (ASs) phosphonate monoester hydrolases...
Significance The versatility of promiscuous enzymes plays a key role in the evolution catalysts. This work addresses molecular mechanism repurposing enzyme by laboratory and reveals that mutations distinct from catalytic machinery reshaped active site. Evolution fine-tuned binding previously disfavored Michaelis complex (E·S), repositioning substrate to enable better charge offset during leaving group departure transition state. functional relies on maintaining reactivity existing groups...
ABSTRACT The Integrator complex (INT) regulates gene expression via premature transcription termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. This attenuation is required for cellular response to external stimuli, cell differentiation and neurodevelopment. How gene-specific regulation achieved by INT in an inducible manner remains unclear. Here, we identify two sites on subunits 13/14 that serve as direct binding hubs diverse sets sequence-specific factors (TFs)...