Biomedical subjects

Hanah Margalit

Publications and source records attributed to Hanah Margalit.

22 records · Page 2Linked to original sources

PubMed2003

Molecular basis for expression of common and rare fragile sites.

Fragile sites are specific loci that form gaps, constrictions, and breaks on chromosomes exposed to partial replication stress and are rearranged in tumors. Fragile sites are classified as rare or common, depending on their induction and frequency within the population. The molecular basis of rare fragile sites is associated with expanded repeats capable of adopting unusual non-B DNA structures that can perturb DNA replication. The molecular basis of common fragile sites was unknown. Fragile sites from R-bands are enriched in flexible sequences relative to nonfragile regions from the same chromosomal bands. Here we cloned FRA7E, a common fragile site mapped to a G-band, and revealed a significant difference between its flexibility and that of nonfragile regions mapped to G-bands, similar to the pattern found in R-bands. Thus, in the entire genome, flexible sequences might play a role in the mechanism of fragility. The flexible sequences are composed of interrupted runs of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication. These sequences show similarity to the AT-rich minisatellite repeats that underlie the fragility of the rare fragile sites FRA16B and FRA10B. We further demonstrate that the normal alleles of FRA16B and FRA10B span the same genomic regions as the common fragile sites FRA16C and FRA10E. Our results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.

Alleles↗

PubMed2003

Insights from MHC-bound peptides.

Cytotoxic T cells recognize short antigenic peptides, the processing products of protein antigens, when they are bound to major histocompatibility complex (MHC) class I molecules. Peptide binding to MHC molecules has been studied extensively in numerous laboratories, providing vast amounts of sequence and structure data that have been used as a rich source for bioinformatic research. MHC-bound peptides and their flanking sequences provide information about the sequence requirements of the different processing stages, in particular, the cleavage by the proteasome and the binding to MHC molecules. Elucidation of these sequence requirements sheds light on the evolutionary forces that have shaped and designed these peptides, and should lead to the development of an integrative predictive algorithm. Remarkably, the peptide sequence and structure data are also valuable for the study of biological questions that are apparently unrelated to cellular immunity, namely, sequence-structure relationship and genome annotation. Here we describe our computational analyses of MHC-bound peptides, applied to all these biological topics.

Allergy and Immunology↗

PubMed2002

PeCoP: automatic determination of persistently conserved positions in protein families.

UNLABELLED: PeCoP is a WWW-based service which accepts a protein sequence, and reports positions that are conserved in close and distant sequence family members. The collation of family members is performed using iterative PSI-BLAST runs. Examining positional conservation in close and distant family members enables a better selection of positions that may play a role in determining the protein's structure and function. AVAILABILITY: http://bioinformatics.org/pecop CONTACT: idoerg@burnham.org SUPPLEMENTARY INFORMATION: http://bioinformatics.org/pecop/about_pecop

Amino Acid Sequence↗

PubMed2002

Persistently conserved positions in structurally similar, sequence dissimilar proteins: roles in preserving protein fold and function.

Many protein pairs that share the same fold do not have any detectable sequence similarity, providing a valuable source of information for studying sequence-structure relationship. In this study, we use a stringent data set of structurally similar, sequence-dissimilar protein pairs to characterize residues that may play a role in the determination of protein structure and/or function. For each protein in the database, we identify amino-acid positions that show residue conservation within both close and distant family members. These positions are termed "persistently conserved". We then proceed to determine the "mutually" persistently conserved (MPC) positions: those structurally aligned positions in a protein pair that are persistently conserved in both pair mates. Because of their intra- and interfamily conservation, these positions are good candidates for determining protein fold and function. We find that 45% of the persistently conserved positions are mutually conserved. A significant fraction of them are located in critical positions for secondary structure determination, they are mostly buried, and many of them form spatial clusters within their protein structures. A substitution matrix based on the subset of MPC positions shows two distinct characteristics: (i) it is different from other available matrices, even those that are derived from structural alignments; (ii) its relative entropy is high, emphasizing the special residue restrictions imposed on these positions. Such a substitution matrix should be valuable for protein design experiments.

Amino Acid Motifs↗