Biomedical subjects

D A Hinds

Publications and source records attributed to D A Hinds.

5 recordsLinked to original sources

PubMed1998

A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

Chromosome Mapping↗

PubMed1996

From structure to sequence and back again.

With a simple lattice model and sequence design algorithm, we can design sequences to fit arbitrary compact globular structures. We judged the success of the design algorithm by performing exhaustive conformational searches to determine if a designed sequence's lowest energy conformation matched the target for which it was designed. Designed sequences tend to be much better optimized for their targets than a natural sequence is optimized for its lowest energy model conformation. We examined the effect of varying the number of available amino acid types on the success of the design method. It was more difficult but not impossible to successfully design discriminating sequences using fewer amino acid types.

Algorithms↗

PubMed1994

Exploring conformational space with a simple lattice model for protein structure.

We present a low resolution lattice model for which we can exhaustively generate all possible compact backbone conformations for small proteins. Using simple structural and energetic criteria, for a variety of proteins, we can select for lattice structures that have significant similarities with their known native structures. Our energetic parameters are based on pairwise amino acid contact frequencies in a database of experimentally determined structures. A key step in our method involves the threading of a sequence onto every lattice model, such that a locally optimal pattern of tertiary interactions is formed. We evaluate our results against statistics collected for structures covering all of conformational space, and against statistics collected for permuted sequences. Despite the low resolution of the model, our low energy structures contain many native features. These results indicate that the overall pattern of hydrophobicity of a sequence significantly constrains the range of folds that sequence is likely to adopt.

Algorithms↗

PubMed1993

Phosphorylation of synthetic peptides containing Tyr-Met-X-Met motifs by nonreceptor tyrosine kinases in vitro.

Several tyrosine phosphorylation sites in the insulin receptor kinase substrate IRS-1 are predicted to be within Tyr-Met-X-Met (YMXM) motifs, and synthetic peptides corresponding to these sequences are excellent substrates for the insulin receptor kinase in vitro (Shoelson, S. E., Chatterjee, S., Chaudhuri, M., and White, M. F. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 2027-2031). In this study, YMXM-containing peptides are shown to act as substrates for two members of the nonreceptor subfamily of tyrosine kinases, v-Src and v-Abl (the transforming gene products of Rous sarcoma virus and Abelson murine leukemia virus, respectively). For v-Src, a baculovirus expression system was used which was capable of producing milligram quantities of pure 60-kDa v-Src in Spodoptera frugiperda (Sf9) cells. The source of v-Abl was an Escherichia coli expression vector that produces a fusion protein of glutathione S-transferase with the abl catalytic domain. The synthetic YMXM-containing peptides had among the highest apparent affinities described to date for either tyrosine kinase, with Km values as low as 97 microM for v-Src and v-Abl. Comparisons with the results obtained with the insulin receptor kinase revealed differences in substrate specificity among the enzymes. In particular, v-Src was more tolerant of substitutions at the Met+1 and Met+3 positions in the YMXM motif than either v-Abl or the insulin receptor kinase but was more dependent on the presence of a preceding acidic amino acid. For v-Abl, the presence of threonine at any position in the YMXM motif caused a reduction in catalytic efficiency. Phosphorylated YMXM motifs are recognition elements for binding to the src homology 2 domains of phosphatidylinositol 3'-kinase and additional proteins; hence, differences in specificity of tyrosine kinases toward YMXM-containing proteins may have relevance to downstream signaling events.

Amino Acid Sequence↗

PubMed1992

A lattice model for protein structure prediction at low resolution.

The prediction of the folded structure of a protein from its sequence has proven to be a very difficult computational problem. We have developed an exceptionally simple representation of a polypeptide chain, with which we can enumerate all possible backbone conformations of small proteins. A protein is represented by a self-avoiding path of connected vertices on a tetrahedral lattice, with several amino acid residues assigned to each lattice vertex. For five small structurally dissimilar proteins, we find that we can separate native-like structures from the vast majority of non-native folds by using only simple structural and energetic criteria. This method demonstrates significant generality and predictive power without requiring foreknowledge of any native structural details.

Amino Acid Sequence↗