A5010954635- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Protein Structure and Dynamics
- SARS-CoV-2 and COVID-19 Research
- Cancer-related gene regulation
- Amyotrophic Lateral Sclerosis Research
- Molecular Communication and Nanonetworks
- Endoplasmic Reticulum Stress and Disease
- biodegradable polymer synthesis and properties
- Computational Drug Discovery Methods
- interferon and immune responses
- RNA regulation and disease
- Legionella and Acanthamoeba research
- Ginkgo biloba and Cashew Applications
- Glycosylation and Glycoproteins Research
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- SARS-CoV-2 detection and testing
- RNA and protein synthesis mechanisms
- Bioinformatics and Genomic Networks
- Prion Diseases and Protein Misfolding
- Neurogenetic and Muscular Disorders Research
- Advanced Biosensing Techniques and Applications
- Advancements in Semiconductor Devices and Circuit Design
University of California, San Francisco
2020-2023
Howard Hughes Medical Institute
2014-2022
University of California, Los Angeles
2017-2020
Molecular Biology Consortium
2020
UCLA Health
2015
University of California, Santa Barbara
2014
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the cell receptor angiotensin-converting enzyme (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt ACE2. Cryo-electron microscopy (cryo-EM) revealed one nanobody, Nb6, binds in fully inactive conformation with binding domains locked into their inaccessible down state, incapable...
Significance More than 170 mutations in superoxide dismutase 1 (SOD1) are linked to inherited forms of ALS, and aggregates this protein a pathological feature associated with disease. Although it is accepted that SOD1 gains toxic function the disease state, molecular understanding species lacking. Here, we identify short segment both necessary sufficient for toxicity motor neurons. The crystal structure reveals an out-of-register β-sheet oligomer, providing structural rationale effects mutant ALS.
Seeding, in the context of amyloid disease, is sequential transfer pathogenic protein aggregates from cell-to-cell within affected tissues. The structure seeds provides molecular basis and enables rapid conversion soluble into fibrils. To date, there are no inhibitors that specifically target seeding Parkinson's disease (PD)-associated α-synuclein (α-syn) fibrils, part, due to lack information structural properties pathological seeds. Here we design small peptidic based on atomic core α-syn...
Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting out-of-register β sheets, which may constitute one the toxic species in aggregation related diseases. Here we sought to determine presence such motif islet amyloid polypeptide (IAPP), whose properties are associated with type 2 diabetes. We determined four new crystal structures within IAPP, all forming steric zippers. Most interestingly, fibril core IAPP forms an zipper....
ABSTRACT Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. gains entry into host cells via interaction between its Spike protein the cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this confers potent neutralization viral entry, providing avenue for vaccine design therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt ACE2. By screening...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of spinal motor neurons. Although mutations in dozens proteins have been associated with ALS, enzyme, superoxide dismutase 1 (SOD1) was first protein identified development ALS and accounts for ~20% familial cases. In experimental animals patient samples, mutant SOD1 found cytoplasmic deposits implicating aggregates as toxic entities. Here we discuss various biochemical...
Five different mutants of [Leu-5] Enkephalin YGGFL peptide have been investigated for fibril formation propensities. The early oligomer structures probed with a combination ion-mobility mass spectrometry and computational modeling. two peptides YVIFL YVVFL form oligomers amyloid-like fibrils. YVVFV shows an stage distribution similar to those the previous two, but aggregates are less abundant. Atomic resolution X-ray show modes interactions at dry interface between steric zippers pairs...
The aggregation cascade of disease-related amyloidogenic proteins, terminating in insoluble amyloid fibrils, involves intermediate oligomeric states. structural and biochemical details these oligomers have been largely unknown. Here we report crystal structures variants the cytotoxic oligomer-forming segment residues 28-38 ALS-linked protein, SOD1. reveal three different architectures: corkscrew structure, nontwisting curved sheet structure a steric zipper proto-filament structure. Our work...
Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. At morphological level, these fibers appear similar termed “amyloid.” From x‐ray electron diffraction, we found that adhesive segments of amyloid short sequences which form pairs interdigitated, in‐register beta sheets. These fibrils were long suspected to be disease agents, but evidence suggests at least some neurodegenerative smaller, often...
Abstract Amyloid formation is associated with devastating diseases such as Alzheimer's, Parkinson's and Type‐2 diabetes. The large amyloid deposits found in patients suffering from these have remained difficult to probe by structural means. Recent NMR models also predict heterotypic interactions distinct peptide fragments but limited evidence of packed sheets observed solution. Here we characterize two segments the protein β (Aβ) known form fibrils Alzheimer's disease patients. We designed...
Abstract Pathogens often secrete proteins or nucleic acids that mimic the structure and/or function of molecules expressed in their hosts. Molecular mimicry empowers pathogens to subvert critical host processes and establish infection. We report intracellular bacterium Legionella pneumophila secretes toxin SidI (substrate icm/dot transporter I), which possesses a transfer RNA (tRNA)-like shape functions as mannosyl transferase. The 3.1 Å cryo-EM reveals an N-terminal domain exhibits...
Abstract The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation the ISR underlies age-related diseases. signaling downregulates translation and activates expression stress-responsive factors that promote return homeostasis is initiated by inhibition decameric guanine nucleotide exchange factor eIF2B. Conformational assembly transitions regulate eIF2B activity, allosteric mechanisms controlling these dynamic mediating therapeutic...
Abstract The Integrated Stress Response (ISR) enables cells to survive a variety of acute stresses, but chronic activation the ISR underlies age-related diseases. signaling down-regulates translation and activates expression stress-responsive factors that promote return homeostasis, is initiated by inhibition decameric guanine nucleotide exchange factor eIF2B. Conformational assembly transitions regulate eIF2B activity, allosteric mechanisms controlling these dynamic are unknown. Using...