A5018406467- Heat shock proteins research
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- Advanced Electron Microscopy Techniques and Applications
- Cancer therapeutics and mechanisms
- Bacterial Genetics and Biotechnology
- DNA and Nucleic Acid Chemistry
- Computational Drug Discovery Methods
- Toxin Mechanisms and Immunotoxins
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Hormonal Regulation and Hypertension
- RNA Research and Splicing
- Bioinformatics and Genomic Networks
- Plant Genetic and Mutation Studies
- Microbial Metabolic Engineering and Bioproduction
- Coenzyme Q10 studies and effects
- Biochemical and Molecular Research
- Tuberculosis Research and Epidemiology
- Estrogen and related hormone effects
Baylor College of Medicine
2015-2024
NYU Langone Health
2016
Yale University
1998-2005
Howard Hughes Medical Institute
1998-2000
University of Oxford
1996-1997
Cell survival under severe thermal stress requires the activity of ClpB (Hsp104) AAA+ chaperone that solubilizes and reactivates aggregated proteins in concert with DnaK (Hsp70) system. How protein disaggregation is achieved whether solely dependent on ClpB-mediated elimination aggregates or also reactivation has been unclear. We engineered a variant, BAP, which associates ClpP peptidase thereby converted into degrading disaggregase. BAP translocates substrates through its central pore...
Heat shock protein (Hsp) 104 is a ring-forming, protein-remodeling machine that harnesses the energy of ATP binding and hydrolysis to drive disaggregation. Although Hsp104 an active ATPase, recovery functional requires species-specific cooperation Hsp70 system. However, like Hsp104, which recognizes aggregated aggregation-prone proteins, making it difficult differentiate mechanistic roles during Mapping Hsp70-binding sites in yeast using peptide array technology photo–cross-linking revealed...
Abstract Loss of protein function is a driving force ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as dominant chaperone in haematopoietic stem and progenitor cells. Depletion PPIA accelerates cell found that proteins with intrinsically disordered regions (IDRs) are frequent substrates. IDRs facilitate interactions other nucleic acids can trigger liquid–liquid phase separation. Over 20% substrates involved the formation supramolecular membrane-less...
Coumarin antibiotics, such as clorobiocin, novobiocin, and coumermycin A1, inhibit the supercoiling activity of gyrase by binding to B (GyrB) subunit. Previous crystallographic studies a 24-kDa N-terminal domain GyrB from E. coli complexed with novobiocin cyclothialidine analogue have shown that both ligands act at ATP-binding site. Clorobiocin is natural antibiotic isolated several Streptomyces strains differs in methyl group 8 position coumarin ring replaced chlorine atom, carbamoyl 3'...
Hsp104 is a ring-forming AAA+ machine that recognizes both aggregated proteins and prion-fibrils as substrates and, together with the Hsp70 system, remodels in an ATP-dependent manner. Whereas ability to disaggregate dependent on M-domain, location of M-domain controversial its exact function remains unknown. Here we present cryoEM structures two variants crosslinked noncrosslinked form, addition structure functional chimera harboring T4 lysozyme within helix L2. Unexpectedly, found our has...
The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in regulation metabolism. Most studies have found it be an inhibitor oxidative phosphorylation (OXPHOS) and inducer Warburg phenotype cancer cells. However, others reported opposite, there is no consensus on relevant TRAP1 interactors. This calls for a more comprehensive analysis interactome how metabolism mutually affect each other.We show that disruption...
FtsH-related AAA proteases are conserved membrane-anchored, ATP-dependent molecular machines, which mediate the processing and turnover of soluble membrane-embedded proteins in eubacteria, mitochondria, chloroplasts. Homo- hetero-oligomeric proteolytic complexes exist, composed homologous subunits harboring an ATPase domain family H41 metallopeptidase domain. Mutations mitochondrial m-AAA have been associated with different neurodegenerative disorders human, raising questions on functional...
<ns4:p>Proteins must adopt a defined three-dimensional structure in order to gain functional activity, or they? An ever-increasing number of intrinsically disordered proteins and amyloid-forming polypeptides challenge this dogma. While molecular chaperones proteases are traditionally associated with protein quality control inside the cell, it is now apparent that not only promote folding “forward” direction by facilitating preventing misfolding aggregation, but also facilitate unfolding even...
ClpB is a ring-forming, ATP-dependent protein disaggregase that cooperates with the cognate Hsp70 system to recover functional from aggregates. How harnesses energy of ATP binding and hydrolysis facilitate mechanical unfolding previously aggregated, stress-damaged proteins remains unclear. Here, we present crystal structures D2 domain in nucleotide-bound -free states, fitted cryoEM structure hexamer ring, which provide structural understanding power stroke drives translocation through...
Significance Mitochondrial heat-shock protein of 90 kDa (Hsp90) (TRAP1) promotes cell survival and is essential for neoplastic growth. Exploiting human TRAP1 drug development requires detailed structural mechanistic understanding. Whereas adopts different conformations associated with distinct nucleotide states, how the dimer senses bound signals this information to neighboring subunit remains unknown. We show that unliganded forms a previously unobserved coiled-coil found in an...
Hsp104 is a ring-forming, ATP-driven molecular machine that recovers functional protein from both stress-denatured and amyloid-forming aggregates. Although shares common architecture with Clp/Hsp100 unfoldases, different seemingly conflicting 3D structures have been reported. Examining the structure of poses considerable challenges because readily hydrolyzes ATP, whereas ATP analogs can be slowly turned over are often contaminated other nucleotide species. Here, we present single-particle...
The ligand-binding domains of steroid hormone receptors possess a conserved structure with 12 α-helices surrounding central hydrophobic core. On agonist binding, repositioned helix forms pocket 3 (H3) and 5 (H5), where transcriptional coactivators bind. precise molecular interactions responsible for activation these remain to be elucidated. We previously identified H3–H5 interaction that permits progesterone-mediated mutant mineralocorticoid receptor. were intrigued note the potential such...
Abstract Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines survey maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled disaggregase essential for preserving integrity structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) early death in infants, while mutations ATPase domain impair disaggregation with observed loss-of-function correlating...