Protein sequence modules

Conserved protein sequence segments are commonly believed to correspond to functional sites in the protein sequence. A novel approach is proposed to profile the changing degree of conservation along the protein sequence, by evaluating the occurrence frequencies of all short oligopeptides of the given sequence in a large proteome database. Thus, a protein sequence conservation profile can be plotted for every protein. The profile indicates where along the sequences the potential functional (conserved) sites are located. The corresponding oligopeptides belonging to the sites are very frequent across many prokaryotic species. Analysis of a representative set of such profiles reveals a common feature of all examined proteins: they consist of sequence modules represented by the peaks of conservation. Typical size of the modules (peak-to-peak distance) is 25-30 amino acid residues.     

Formation of the local secondary structure of proteins: local sequence or environment

An analysis of the occurrence of tetrapeptides in 35 globular proteins for alpha-helix, beta-structure and coil was performed. We concluded that: the conformation of a short polypeptide segment cannot be determined on the basis of the knowledge of the amino acid sequence only; local structures of a protein are formed as the result of interactions within the whole structural domain of the protein as well as interactions with the environment.     

Inference of splicing regulatory activities by sequence neighborhood analysis

Sequence-specific recognition of nucleic-acid motifs is critical to many cellular processes. We have developed a new and general method called Neighborhood Inference (NI) that predicts sequences with activity in regulating a biochemical process based on the local density of known sites in sequence space. Applied to the problem of RNA splicing regulation, NI was used to predict hundreds of new exonic splicing enhancer (ESE) and silencer (ESS) hexanucleotides from known human ESEs and ESSs. These predictions were supported by cross-validation analysis, by analysis of published splicing regulatory activity data, by sequence-conservation analysis, and by measurement of the splicing regulatory activity of 24 novel predicted ESEs, ESSs, and neutral sequences using an in vivo splicing reporter assay. These results demonstrate the ability of NI to accurately predict splicing regulatory activity and show that the scope of exonic splicing regulatory elements is substantially larger than previously anticipated. Analysis of orthologous exons in four mammals showed that the NI score of ESEs, a measure of function, is much more highly conserved above background than ESE primary sequence. This observation indicates a high degree of selection for ESE activity in mammalian exons, with surprisingly frequent interchangeability between ESE sequences.     

Midfacial duplication: a rare malformation sequence

A child with duplicate maxilla is presented, along with a review of the literature of similar cases. Partial duplications of the maxilla are frequently accompanied by cleft lip and palate, multiple uvulae, hypertelorbitism, and intracranial anomalies with hydrocephalus. Theories of the morphopathogenesis for this malformation sequence are discussed.