A5073749793- Nuclear Structure and Function
- RNA Research and Splicing
- Cellular transport and secretion
- Genomics and Chromatin Dynamics
- RNA Interference and Gene Delivery
- RNA regulation and disease
- Advanced biosensing and bioanalysis techniques
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Fungal and yeast genetics research
- DNA Repair Mechanisms
- Endoplasmic Reticulum Stress and Disease
- HIV Research and Treatment
- Genetics, Aging, and Longevity in Model Organisms
- Renal and related cancers
- Genetic Neurodegenerative Diseases
- RNA modifications and cancer
- Amyotrophic Lateral Sclerosis Research
- Cancer-related gene regulation
- Plant Stress Responses and Tolerance
- Force Microscopy Techniques and Applications
- Erythrocyte Function and Pathophysiology
- Lipid metabolism and biosynthesis
- Nanopore and Nanochannel Transport Studies
- Wnt/β-catenin signaling in development and cancer
Yale University
2016-2025
Johns Hopkins Medicine
2021
Johns Hopkins University
2021
University of New Haven
2015
Washington University in St. Louis
2011-2012
University of Alberta
2001-2007
Rockefeller University
2006-2007
Howard Hughes Medical Institute
2006-2007
Fluorescence nanoscopy, or super-resolution microscopy, has become an important tool in cell biological research. However, because of its usually inferior resolution the depth direction (50–80 nm) and rapidly deteriorating thick samples, practical application been effectively limited to two dimensions thin samples. Here, we present development whole-cell 4Pi single-molecule switching nanoscopy (W-4PiSMSN), optical nanoscope that allows imaging three-dimensional (3D) structures at 10- 20-nm...
A single particle cryo-EM reconstruction of an ∼160-kD N-terminal fragment the lipid transport protein VPS13 reveals ∼160-Å long channel lined with hydrophobic residues suitable for solubilizing multiple fatty acid moieties. The structure suggests that and related proteins, like autophagy ATG2, can act as bridges between organelle membranes to allow bulk flow organelles.
Natively unfolded linkers facilitate nuclear membrane protein import.
Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion remains unexplained. Recently, it was discovered that mutations NUP93 and NUP205, encoding 2 proteins the inner ring subunit nuclear pore complex (NPC), cause SRNS. Here, we describe in genes 4 components outer rings NPC, namely NUP107, NUP85, NUP133, NUP160, 13 families with Using coimmunoprecipitation...
The integrity of the nuclear membranes coupled to selective barrier pore complexes (NPCs) are essential for segregation nucleoplasm and cytoplasm. Mechanical membrane disruption or perturbation NPC assembly triggers an ESCRT-dependent surveillance system that seals pores: how these pores sensed sealed is ill defined. Using a budding yeast model, we show ESCRT Chm7 integral inner (INM) protein Heh1 spatially segregated by transport, with being actively exported Xpo1/Crm1. Thus, exposure INM...
Nuclear accumulation of CHMP7 leads to multiple cellular pathologies that can be mitigated via ASOs in familial and sporadic ALS iPSNs.
Nuclear pore complexes (NPCs) form gateways that control molecular exchange between the nucleus and cytoplasm. They impose a diffusion barrier to macromolecules enable selective transport of nuclear receptors with bound cargo. The underlying mechanisms establish these permeability properties remain be fully elucidated but require unstructured proteins rich in Phe-Gly (FG)-repeat domains different types, such as FxFG GLFG. While physical modeling vitro approaches have provided framework for...
Nuclear transport is facilitated by the Pore Complex (NPC) and essential for life in eukaryotes. The NPC a long-lived exceptionally large structure. We asked whether quality control compromised aging mitotic cells. Our images of single yeast cells during aging, show that abundance several components assembly factors decreases. Additionally, single-cell histories reveal better maintain those are longer lived. presence herniations at nuclear envelope aged suggests misassembled NPCs accumulated...
Increasing evidence has suggested that the HIV-1 capsid enters nucleus in a largely assembled, intact form. However, not much is known about how cone-shaped interacts with nucleoporins (NUPs) nuclear pore for crossing complex. Here, we elucidate NUP153 binds by engaging assembled protein (CA) lattice. A bipartite motif containing both canonical and noncanonical interaction modules was identified at C-terminal tail region of NUP153. The cargo-targeting phenylalanine-glycine (FG) engaged CA...
Emerging evidence suggests that the nuclear pore complex can have unique compositions and distinct nucleoporin functions in different cells. Here, we show Nup107, a key component of NPC scaffold, varies expression over development: it is expressed at higher levels blastula compared to gastrula suggesting critical role prior gastrulation. We find depletion Nup107 affects differentiation early germ layers leading an expansion ectoderm expense endoderm mesoderm. By analyzing RNAseq time course,...
The nuclear pore complex (NPC) is a multicomponent structure containing subset of proteins that bind transport factors or karyopherins and mediate their movement across the envelope. By altering expression single nucleoporin gene, NUP53, we showed overproduction Nup53p altered had profound effect on membrane. Strikingly, conventional immunoelectron microscopy analysis revealed excess entered nucleus associated with Here, induced formation intranuclear, tubular membranes later formed...
Nuclear envelope herniations (blebs) containing FG-nucleoporins and ubiquitin are the phenotypic hallmark of Torsin ATPase manipulation. Both dynamics blebbing connection to nuclear pore biogenesis remain poorly understood. We employ a proteomics-based approach identify myeloid leukemia factor 2 (MLF2) as luminal component bleb. Using an MLF2-based live-cell imaging platform, we demonstrate that occurs rapidly synchronously immediately after reformation during mitosis. Bleb formation is...
Mechanisms that control nuclear membrane remodeling are essential to maintain the integrity of nucleus but remain be fully defined. Here, we identify a phosphatidic acid (PA)–binding capacity in envelope (NE)–specific ESCRT, Chm7, budding yeast. Chm7’s interaction with PA-rich membranes is mediated through conserved hydrophobic stretch amino acids, which confers recruitment NE manner independent required for LAP2-emerin-MAN1 (LEM) domain protein Heh1 (LEM2). Consistent functional importance...
The DNA-origami technique has enabled the engineering of transmembrane nanopores with programmable size and functionality, showing promise in building biosensors synthetic cells. However, it remains challenging to build large (>10 nm), functionalizable that spontaneously perforate lipid membranes. Here, we take advantage pneumolysin (PLY), a bacterial toxin potently forms wide ring-like channels on cell membranes, construct hybrid DNA-protein nanopores. This PLY-DNA-origami complex, which...
Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP necessary for degradation via proteasome lysosome. IBMPFD/ALS mutations disrupt autophagosome endosome maturation resulting vacuolation, weakness muscle atrophy. To understand regulation autophagy VCP-IBM muscle, we...
Nuclear pore complexes (NPCs) are essential protein assemblies that span the nuclear envelope and establish nuclear-cytoplasmic compartmentalization. We have investigated mechanisms control NPC number in mother daughter cells during asymmetric division of budding yeast. By simultaneously tracking existing NPCs newly synthesized protomers (nups) through anaphase, we uncovered a pool central channel nup Nsp1 is actively targeted to bud association with endoplasmic reticulum. Bud targeting...