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A major challenge of computational protein design is the creation of novel proteins with arbitrarily chosen three-dimensional structures. Here, we used a general computational strategy that iterates between sequence design and structure prediction to design a 93-residue alpha/beta protein called Top7 with a novel sequence and topology. Top7 was found(More)
Many proteins involved in pre-mRNA processing contain one or more copies of a 70-90-amino-acid alphabeta module called the ribonucleoprotein domain. RNA maturation depends on the specific recognition by ribonucleoproteins of RNA elements within pre-mRNAs and small nuclear RNAs. The human U1A protein binds an RNA hairpin during splicing, and regulates its(More)
Hairpin loops are important structural elements of RNA, helping to define the three-dimensional structure of large RNAs and providing potential nucleation sites for RNA folding and interaction with other nucleic acids and proteins. Little, however, is known about the conformation of RNA hairpins, most of what we know coming from transfer RNA crystal(More)
The RNA response element TAR plays a critical role in HIV replication by providing a binding site for the recruitment of the viral transactivator protein Tat. Using a structure-guided approach, we have developed a series of conformationally-constrained cyclic peptides that act as structural mimics of the Tat RNA binding region and block Tat-TAR interactions(More)
Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic(More)
To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least(More)
Eukaryotes and archaea use two sets of specialized ribonucleoproteins (RNPs) to carry out sequence-specific methylation and pseudouridylation of RNA, the two most abundant types of modifications of cellular RNAs. In eukaryotes, these protein-RNA complexes localize to the nucleolus and are called small nucleolar RNPs (snoRNPs), while in archaea they are(More)
Achieving atomic-level resolution in the computational design of a protein structure remains a challenging problem despite recent progress. Rigorous experimental tests are needed to improve protein design algorithms, yet studies of the structure and dynamics of computationally designed proteins are very few. The NMR structure and backbone dynamics of a(More)
Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in(More)