A5076214491- Hedgehog Signaling Pathway Studies
- Photoreceptor and optogenetics research
- Epigenetics and DNA Methylation
- Lipid Membrane Structure and Behavior
- Advanced NMR Techniques and Applications
- Genomics and Chromatin Dynamics
- Genetic and Kidney Cyst Diseases
- Electron Spin Resonance Studies
- Cholesterol and Lipid Metabolism
- Molecular spectroscopy and chirality
- RNA and protein synthesis mechanisms
- Neuroscience and Neuropharmacology Research
- Kruppel-like factors research
- Drug Transport and Resistance Mechanisms
- Genetic and rare skin diseases.
- Hippo pathway signaling and YAP/TAZ
- Aldose Reductase and Taurine
- Spectroscopy and Quantum Chemical Studies
- Cancer-related Molecular Pathways
- Hemoglobin structure and function
- RNA regulation and disease
- Nutrition, Genetics, and Disease
- Alzheimer's disease research and treatments
- Chromatin Remodeling and Cancer
- Prion Diseases and Protein Misfolding
Stanford University
2017-2025
University of California, Santa Barbara
2012-2022
To uncover regulatory mechanisms in Hedgehog (Hh) signaling, we conducted genome-wide screens to identify positive and negative pathway components validated top hits using multiple signaling differentiation assays two different cell types. Most regulators identified our screens, including Rab34, Pdcl, Tubd1, were involved ciliary functions, confirming the central role for primary cilia Hh signaling. Negative included Megf8, Mgrn1, an unannotated gene encoding a tetraspan protein named...
Previously we proposed that transmission of the hedgehog signal across plasma membrane by Smoothened is triggered its interaction with cholesterol (Luchetti et al., 2016). But how cholesterol, an abundant lipid, regulated tightly enough to control a signaling system can cause birth defects and cancer? Using toxin-based sensors distinguish between distinct pools find activation Hedgehog are driven biochemically-defined, small fraction termed accessible cholesterol. Increasing accessibility...
Smoothened (SMO) transduces the Hedgehog (Hh) signal across plasma membrane in response to accessible cholesterol. Cholesterol binds SMO at two sites: one extracellular cysteine-rich domain (CRD) and a second transmembrane (TMD). How these sterol-binding sites mediate activation ligand Sonic (SHH) remains unknown. We find that mutations CRD (but not TMD) reduce fold increase activity triggered by SHH. SHH also promotes photocrosslinking of sterol analog intact cells. In contrast, binding TMD...
Significance Amyloid fibril formation is a key process accompanying many neurodegenerative diseases. Oligomers formed in the early stages of aggregation have been thought to play role disease effects, but their studies are challenging. We use site-specific measurements surface water diffusion, protein segmental dynamics, and interstrand packing track tau processes situ. Our study reveals that accompanied by dramatic structural transformation within minutes initiating aggregation, followed...
A long-standing mystery in vertebrate Hedgehog signaling is how Patched 1 (PTCH1), the receptor for ligands, inhibits activity of Smoothened, protein that transmits signal across membrane. We previously proposed (Kinnebrew et al., 2019) PTCH1 Smoothened by depleting accessible cholesterol from ciliary Using a new imaging-based assay to directly measure transport PTCH1, we find depletes outer leaflet plasma This terminated binding ligands or dissipation transmembrane potassium gradient. These...
Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes endoplasmic reticulum (ER). When ER levels are low, Scap activates SREBPs, transcription factors upregulate genes for cholesterol, fatty acids, and triglycerides. rise, sterol to triggering conformational changes prevent activation SREBPs halting lipids. To achieve molecular understanding how regulates Scap/SREBP machine identify therapeutics dysregulated lipid metabolism,...
Rising temperatures and water scarcity caused by climate change are increasingly exposing our cells tissues to ionic stress, a consequence of elevated cytoplasmic strength that can disrupt protein, organelle, genome function. Here, we unveil single-protein mechanism for sensing mitigation in animal cells, one is notably different from the analogous high osmolarity glycerol kinase cascade yeast. The Rel family transcription factor NFAT5 directly senses intracellular using C-terminal...
E3 ubiquitin ligases play a crucial role in modulating receptor stability and signaling at the cell surface, yet mechanisms governing their substrate specificity remain incompletely understood. Mahogunin Ring Finger 1 (MGRN1) is membrane-tethered ligase that finetunes sensitivity by targeting surface receptors for ubiquitination degradation. Unlike cytosolic ligases, E3s require transmembrane adapters to selectively recognize regulate receptors, few such have been studied detail. While MGRN1...
Patched1 (PTCH1) is a tumor suppressor protein of the mammalian Hedgehog (HH) signaling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits G protein–coupled receptor Smoothened (SMO) via debated mechanism involving modulating ciliary cholesterol accessibility. Using extensive molecular dynamics simulations free energy calculations to evaluate transport through PTCH1, we find an energetic barrier ~15 20 kilojoule per mole for export. In silico data are coupled vivo...
SUMMARY Homeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense enable adaptation to stress remain poorly understood in animals. We find the transcription factor NFAT5 directly senses solution using a C-terminal intrinsically disordered region. Both intact cells purified system, forms dynamic, reversible biomolecular condensates response increasing strength. This self-associative property, conserved from insects...
Smoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer birth defects. SMO responds accessible cholesterol in ciliary membrane, translocating it via longitudinal tunnel its extracellular domain. Reaching complete mechanistic understanding translocation process would help development therapies. Competing hypotheses based on available structures support entry from outer inner membrane leaflets, but exact mechanism remains...
Patched1 (PTCH1) is the principal tumour suppressor protein of mammalian Hedgehog (HH) signalling pathway, implicated in embryogenesis and tissue homeostasis. PTCH1 inhibits Class F G protein-coupled receptor Smoothened (SMO) via a debated mechanism involving modulating accessible cholesterol levels within ciliary membranes. Using extensive molecular dynamics (MD) simulations free energy calculations to evaluate transport through PTCH1, we find an energetic barrier ~15-20 kJ mol