A5078858753- Nuclear Structure and Function
- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- Cancer, Hypoxia, and Metabolism
- Drug Transport and Resistance Mechanisms
- Enzyme Structure and Function
- Methane Hydrates and Related Phenomena
- Seismic Waves and Analysis
- Microtubule and mitosis dynamics
- Ionosphere and magnetosphere dynamics
- Earthquake Detection and Analysis
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Alzheimer's disease research and treatments
- Liver Disease Diagnosis and Treatment
- Advanced Electron Microscopy Techniques and Applications
- Trace Elements in Health
- DNA Repair Mechanisms
- ATP Synthase and ATPases Research
- Neuroscience and Neuropharmacology Research
- Drug-Induced Hepatotoxicity and Protection
- S100 Proteins and Annexins
- Protein Structure and Dynamics
The University of Texas Southwestern Medical Center
2014-2025
Southwestern Medical Center
2018-2024
University of Pennsylvania
2018-2020
Washington University in St. Louis
2012-2014
ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated cytosol. However, determinants localization and cellular insults that promote are incompletely understood. Here, we show putative Nuclear Export Signal (NES) not required for egress TDP-43. Moreover, when domain which contains NES fused reporter protein, YFP, presence sufficient mediate exclusion...
Nuclear export receptor CRM1 binds highly variable nuclear signals (NESs) in hundreds of different cargoes. Previously we have shown that NESs both polypeptide orientations (Fung et al., 2015). Here, show crystal structures bound to eight additional which reveal diverse conformations range from loop-like all-helix, occupy extents the invariant NES-binding groove. Analysis all NES 5-6 distinct backbone where only conserved secondary structural element is one turn helix central portion All...
The Chromosome Region of Maintenance 1 (CRM1) protein mediates nuclear export hundreds proteins through recognition their signals (NESs), which are highly variable in sequence and structure. plasticity the CRM1-NES interaction is not well understood, as there many NES sequences that seem incompatible with structures NES-bound CRM1 groove. Crystal bound to two different NESs unusual showed peptides binding groove opposite orientation (minus) previously studied (plus). Comparison minus plus...
Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This exemplified the phosphate-sensing transcription factor Pho4, requires phosphorylation for export yeast exportin Msn5. Here, we present a high resolution cryogenic-electron microscopy structure showing phosphorylated 35-residue signal binds concave surface Msn5 through two Pho4 phospho-serines that align with basic...
Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools enable the discovery potential drug targets within schistosomes. Thus, praziquantel has remained frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted genome-wide study in S. mansoni using human druggable genome as bioinformatic template to identify essential genes schistosomes bearing similarity catalogued targets. Then,...
CRM1 (Exportin1/XPO1) exports hundreds of broadly functioning protein cargoes out the cell nucleus by binding to their classical nuclear export signals (NESs). The 8- 15-amino-acid-long NESs contain four five hydrophobic residues and are highly diverse in both sequence CRM1-bound structure. Here we examine relationship between activities 24 different NES peptides cells CRM1-NES affinities. We found that affinity activity linearly correlated for with dissociation constants ( K d s) tens...
IMPORTIN-4, the primary nuclear import receptor of core histones H3 and H4, binds H3–H4 dimer histone chaperone ASF1 prior to import. However, how H3–H3–ASF1 is recognized for transport cannot be explained by available crystal structures IMPORTIN-4–histone tail peptide complexes. Our 3.5-Å IMPORTIN-4–H3–H4–ASF1 cryoelectron microscopy structure reveals full complex shows a binding mode different from suggested previous structures. The N-terminal half IMPORTIN-4 clamps globular domain αN...
Abstract During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to Retriever complex. Despite its importance, mechanisms underlying this interaction have remained elusive. Here, we report structure Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our reveals that C-terminal tail SNX17 engages with a highly conserved interface between VPS35L and VPS26C subunits Retriever. Through...
During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to Retriever complex. Despite its importance, mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in basal state, with FERM domain sequestering C-terminal tail. The binding displaces...
Previously, we showed that the nuclear import receptor Importin-9 wraps around H2A-H2B core to chaperone and transport it from cytoplasm nucleus. However, unlike most systems where RanGTP dissociates cargoes their importins, binds stably Importin-9•H2A-H2B complex, formation of ternary RanGTP•Importin-9•H2A-H2B complex facilitates release assembling nucleosome. It was unclear how cargo can bind simultaneously an importin, interactions three components position for release. Here, show cryo-EM...
Previous studies demonstrated that L-Fabp KO mice are more susceptible to lithogenic diet (LD)-induced gallstones because of altered hepatic cholesterol metabolism and increased canalicular secretion. Other liver-specific deletion microsomal triglyceride transfer protein (Mttp-LKO) reduced LD-induced gallstone formation by increasing biliary phospholipid Here we show with combined (i.e., DKO mice) protected from formation. Following 2 weeks LD feeding, 73% WT 100% developed versus 18%...
Padavannil et al. 2019 show that Importin-9 (Imp9) transports Histones H2A-H2B from the cytoplasm to nucleus using a non-canonical mechanism whereby binding of GTP-bound Ran GTPase (RanGTP) fails evict cargo. Instead, stable complex forms, comprised equimolar RanGTP, Imp9, and H2A-H2B. Unlike binary Imp9•H2A-H2B complex, this RanGTP•Imp9•H2A-H2B ternary can release an assembling nucleosome. Here, we define molecular basis for RanGTP-activated nucleosome assembly by Imp9. We use...
Summary Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This exemplified the phosphate-sensing transcription factor Pho4, requires phosphorylation for export yeast exportin Msn5. Unlike traditional hydrophobic signal (NES) utilized Exportin-1/XPO1 system, cryogenic-electron microscopy structures reveal that Pho4 presents a novel, phosphorylated 35-residue NES interacts...