A5091552955- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Protein Structure and Dynamics
- RNA Research and Splicing
- RNA modifications and cancer
- Genomics and Rare Diseases
- Enzyme Structure and Function
- Cellular transport and secretion
- Evolution and Genetic Dynamics
- CRISPR and Genetic Engineering
- Immunodeficiency and Autoimmune Disorders
- Genomics and Chromatin Dynamics
- Ion Channels and Receptors
- Genetic Associations and Epidemiology
- DNA and Nucleic Acid Chemistry
- Biomedical Text Mining and Ontologies
- Ubiquitin and proteasome pathways
- Trypanosoma species research and implications
- Blood Coagulation and Thrombosis Mechanisms
- Autophagy in Disease and Therapy
- Mass Spectrometry Techniques and Applications
- Pediatric health and respiratory diseases
- Inflammasome and immune disorders
- Complement system in diseases
- Sepsis Diagnosis and Treatment
Max Planck Institute of Molecular Cell Biology and Genetics
2018-2025
Center for Systems Biology Dresden
2021-2025
TU Dresden
2022-2025
Harvard University
2016-2023
Brigham and Women's Hospital
2018-2023
Boston Children's Hospital
2019
Weizmann Institute of Science
2009-2018
Center for Systems Biology
2016-2018
Hungarian Academy of Sciences
2008-2009
Institute of Molecular Life Sciences
2008-2009
Coevolutionary sequence analysis has become a commonly used technique for de novo prediction of the structure and function proteins, RNA, protein complexes. We present EVcouplings framework, fully integrated open-source application Python package coevolutionary analysis. The framework enables generation alignments, calculation evaluation evolutionary couplings (ECs), mutation effects. combination an easy to use, flexible command line interface underlying modular makes full power analyses...
Nucleoside-based cofactors are presumed to have preceded proteins. The Rossmann fold is one of the most ancient and functionally diverse protein folds, enzymes utilize nucleoside-based cofactors. We analyzed an omnipresent ribose-binding interaction: a carboxylate side chain at tip second β-strand (β2-Asp/Glu). identified canonical motif, defined by β2-topology unique geometry. latter relates interaction being bidentate (both ribose hydroxyls interacting with oxygens), angle between ribose,...
Systematic mappings of the effects protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins tolerant to most amino acid substitutions, including substitutions in positions highly conserved nature. To obtain a more realistic distribution mutations, we applied laboratory drift comprising 17 rounds random mutagenesis and selection M.HaeIII, DNA methyltransferase. During this drift, multiple gradually accumulated. Deep sequencing drifted gene...
Abundant and essential motifs, such as phosphate-binding loops (P-loops), are presumed to be the seeds of modern enzymes. The Walker-A P-loop is absolutely in NTPase enzymes, mediating binding, transfer terminal phosphate groups NTPs. However, function depends on many additional active-site residues placed throughout protein’s scaffold. Can motifs P-loops confer a simpler context? We applied phylogenetic analysis that yielded sequence logo putative ancestral element: β-strand connected an...
Localized translation is vital to polarized cells and requires precise robust distribution of different mRNAs ribosomes across the cell. However, underlying molecular mechanisms are poorly understood important players lacking. Here, we discovered a Rab5 effector, five-subunit endosomal RNA/ribosome intermediary (FERRY) complex, that recruits early endosomes through direct mRNA-interaction. FERRY displays preferential binding certain groups transcripts, including encoding mitochondrial...
Abstract The discovery of biomolecular condensates transformed our understanding intracellular compartmentalization molecules. To integrate interdisciplinary scientific knowledge about the function and composition condensates, we developed crowdsourcing condensate database encyclopedia ( cd-code.org ). CD-CODE is a community-editable platform, which includes based on literature, an relevant terms web application. Our platform will accelerate validation facilitate efforts to understand their...
The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). has a modular architecture (Head, Middle, Tail) cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators RNAP II. These rearrangements have been proposed to play role in assembly of preinitiation also contribute mechanism Mediator. In analogy many...
Why do certain proteins evolve much slower than others? We compared not only rates per protein, but also position within individual proteins. For ∼90% of proteins, the distribution positional exhibits three peaks: a peak slow evolving residues, with average log 2 [normalized rate], μ, ca. −2, corresponding primarily to core residues; fast residues (log μ ∼ 0.5) largely surface and very 2) associated disordered segments. However, unique fraction that slowly exhibit negligible peak, −4, rather...
Backbone modifications via insertions and deletions (InDels) may exert dramatic effects, for better (mediating new functions) worse (causing loss of structure and/or function). However, contrary to point mutations (substitutions), our knowledge the evolution structural-functional effects InDels is limited so capability engineer them. We sought assess how deleterious are relative understand mechanisms that mediate their acceptance. Analysis in orthologous protein phylogenies indicated rate...
Abstract Stop codon readthrough events give rise to longer proteins, which may alter the protein’s function, thereby generating short-lasting phenotypic variability from a single gene. In order systematically assess frequency and origin of stop events, we designed library reporters. We introduced premature codons into mScarlet, enabled high-throughput quantification protein synthesis termination errors in E. coli using fluorescent microscopy. found that under stress conditions, occur at...
Intrinsically disordered regions (IDRs) are structurally flexible protein segments with regulatory functions in multiple contexts, such as the assembly of biomolecular condensates. Since IDRs undergo more rapid evolution than ordered regions, identifying homology poorly conserved remains challenging for state-of-the-art alignment-based methods that rely on position-specific conservation residues. Thus, systematic functional annotation and evolutionary analysis have been limited, despite them...
Abstract Increasing insights into how sequence motifs in intrinsically disordered regions (IDRs) provide functions underscore the need for systematic motif detection. Contrary to structured where can be readily identified from alignments, rapid evolution of IDRs limits usage alignment‐based tools reliably detecting within. Here, we developed SHARK‐capture, an alignment‐free detection tool designed difficult‐to‐align regions. SHARK‐capture innovates on word‐based methods by flexibly...
DNA binding specificity of homeodomain transcription factors is critically affected by disordered N-terminal tails (N-tails) that undergo a disorder-to-order transition upon interacting with DNA. The mechanism the process and molecular basis selectivity are largely unknown. coupling between folding Antp NK-2 homeodomains was investigated coarse-grained dynamics simulations using native protein−DNA complex. N-tails were found to decrease stability free proteins competing intramolecular...
Short insertions and deletions (InDels) comprise an important part of the natural mutational repertoire. InDels are, however, highly deleterious, primarily because two-thirds result in frame-shifts. Bypass through slippage over homonucleotide repeats by transcriptional and/or translational infidelity is known to occur sporadically. However, overall frequency bypass its relation sequence composition remain unclear. Intriguingly, occurrence frame-shifts are mechanistically related - occurring...
Abstract Biomolecular condensates are membraneless organelles that can concentrate hundreds of different proteins in cells to operate essential biological functions. However, accurate identification their components remains challenging and biased towards with high structural disorder content focus on self-phase separating (driver) proteins. Here, we present a machine learning algorithm, PICNIC (Proteins Involved CoNdensates In Cells) classify localize biomolecular regardless role condensate...
Protein ubiquitination is central to the regulation of various pathways in eukaryotes. The process and its cellular outcome were investigated hundreds proteins date. Despite this, evolution this regulatory mechanism has not yet been addressed comprehensively. Here, we quantify rates evolutionary changes SUMOylation (Small Ubiquitin-like MOdifier) sites. We estimate time at which they first appeared, compare them acetylation phosphorylation sites unmodified residues. observe that modification...
To identify the genetic cause of disease in a form congenital spinal muscular atrophy and arthrogryposis (CSMAA).A 2-year-old boy was diagnosed with multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, diminished lower limb movement. Whole-exome sequencing (WES) performed on proband family members. In silico modeling protein structure heterologous expression cytotoxicity assays were to validate pathogenicity identified variant.WES revealed homozygous...