Biomedical subjects

Thomas D Goddard

Publications and source records attributed to Thomas D Goddard.

5 recordsLinked to original sources

PubMed2026

A conserved antioxidant defense at the endoplasmic reticulum membrane.

Oxidative protein folding in the endoplasmic reticulum (ER) is essential for eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species. The ER-transmembrane protein that supports ER proteostasis and guards the cytosol for antioxidant defense remains unidentified. Here, we combine AlphaFold2 and functional screens in C. elegans to discover a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting ERGU-1 upregulates H2O2 and NRF2/SKN-1-dependent gene expression. ERGU-1 deficiency also impairs organismal reproduction and behavioral responses to H2O2. Both C. elegans ERGU-1 and human homolog TMEM161B localize to ER membranes, forming reticular networks. Human and Drosophila homologs of ERGU-1 rescue C. elegans mutant phenotypes, demonstrating ancient and conserved functions. In addition, purified ERGU-1 and TMEM161B exhibit redox-modulated oligomeric states. Together, our results reveal an ER-membrane-specific machinery, suggesting a conserved mechanism for maintaining ER redox homeostasis and proteostasis in animal cells.

Animals↗

PubMed2006

Visualizing density maps with UCSF Chimera.

We describe methods for interactive visualization and analysis of density maps available in the UCSF Chimera molecular modeling package. The methods enable segmentation, fitting, coarse modeling, measuring and coloring of density maps for elucidating structures of large molecular assemblies such as virus particles, ribosomes, microtubules, and chromosomes. The methods are suitable for density maps with resolutions in the range spanned by electron microscope single particle reconstructions and tomography. All of the tools described are simple, robust and interactive, involving computations taking only seconds. An advantage of the UCSF Chimera package is its integration of a large collection of interactive methods. Interactive tools are sufficient for performing simple analyses and also serve to prepare input for and examine results from more complex, specialized, and algorithmic non-interactive analysis software. While both interactive and non-interactive analyses are useful, we discuss only interactive methods here.

Bacteriophage T4↗

PubMed2005

Software extensions to UCSF chimera for interactive visualization of large molecular assemblies.

Many structures of large molecular assemblies such as virus capsids and ribosomes have been experimentally determined to atomic resolution. We consider four software problems that arise in interactive visualization and analysis of large assemblies: how to represent multimers efficiently, how to make cartoon representations, how to calculate contacts efficiently, and how to select subassemblies. We describe techniques and algorithms we have developed and give examples of their use. Existing molecular visualization programs work well for single protein and nucleic acid molecules and for small complexes. The methods presented here are proposed as features to add to existing programs or include in next-generation visualization software to allow easy exploration of assemblies containing tens to thousands of macromolecules. Our approach is pragmatic, emphasizing simplicity of code, reliability, and speed. The methods described have been distributed as the Multiscale extension of the UCSF Chimera (www.cgl.ucsf.edu/chimera) molecular graphics program.

Algorithms↗

PubMed2004

Long-range interphase chromosome organization in Drosophila: a study using color barcoded fluorescence in situ hybridization and structural clustering analysis.

We have developed a color barcode labeling strategy for use with fluorescence in situ hybridization that enables the discrimination of multiple, identically labeled loci. Barcode labeling of chromosomes provides long-range path information and allows structural analysis at a scale and resolution beyond what was previously possible. Here, we demonstrate the use of a three-color, 13-probe barcode for the structural analysis of Drosophila chromosome 2L in blastoderm stage embryos. We observe the chromosome to be strongly polarized in the Rabl orientation and for some loci to assume defined positions relative to the nuclear envelope. Our analysis indicates packing approximately 15- to 28-fold above the 30-nm fiber, which varies along the chromosome in a pattern conserved across embryos. Using a clustering implementation based on rigid body alignment, our analysis suggests that structures within each embryo represent a single population and are effectively modeled as oriented random coils confined within nuclear boundaries. We also found an increased similarity between homologous chromosomes that have begun to pair. Chromosomes in embryos at equivalent developmental stages were found to share structural features and nuclear localization, although size-related differences that correlate with the cell cycle also were observed. The methodology and tools we describe provide a direct means for identifying developmental and cell type-specific features of higher order chromosome and nuclear organization.

Animals↗

PubMed2004

UCSF Chimera--a visualization system for exploratory research and analysis.

The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.

Amino Acid Sequence↗