Protein sequences, from genomic sequence

Marcotte, E. M., Pellegrini, M., Ng, H.-L., Rice, D. W., Yeates, T. O., and Eisenberg, D. (1999). Detecting protein function and protein-protein interactions from genome sequences. Science 255, 751-753. 

Detecting Protein Function and Protein-Protein Interactions from Genome Sequences. 

Determining protein function from genomic sequences is a central goal of bioinformatics... 

Marcotte, E. M. et al. 1999. Detecting protein function and protein-protein interactions from genome sequences. Science, 285, 751-753. 

The canonical rubredoxin has been purified from only one hyperthermophile, the archaeon Pyrococcus furiosus The other sequences of hyperthermophilic rubredoxins shown in Fig. 1 are putative proteins derived from genome sequences. Note that while all rubredoxins are highly similar, the hyperthermophilic... 

A variety of domain or motif families occur only as extensions to other domains. The Bruton s tyrosine kinase motif (BTK), for example, is found only at the C terminus of PH domains. Similarly, a C-terminal extension (the S TK X domain) to some subfamilies of serine/threonine kinases (S TK) is not found in isolation. Cases where only the extension, and not the preceding domain, is found are strong evidence that the proteins are wrongly assembled from genomic sequence or else represent partial cDNA sequences (Fig. 9, see Color insert). Indeed, all five proteins annotated in SMART as containing a S TK X domain with no catalytic domain are noted to be fragments in their corresponding sequence database entries. 

Interpretation of results of these studies is still difficult. Results of two-hybrid methods become more useful if they can be coordinated with other approaches. For example, computational methods can predict interactions from genome sequences alone. 11/0 More than 45,000 interactions have been predicted among yeast proteins. Reliable identification of such motifs as DNA-binding domains and Ca2+- binding domains can complement two-hybrid analysis.11 The yeast genome is predicted to contain 162 coiled-coil sequences and at least 213 unique interactions between them.0 Examination of sequences of protein families in the Protein Data Bank (PDB) led to prediction of 8151 interactions of 664 types between protein families in yeast.P... 

The preferred modem procedure for investigating an enzyme mechanism is to identify a protein in a genome sequence, clone and express it, solve the crystal and/or solution structures, guess the mechanism, and then confirm it by site-directed mutagenesis and kinetics. The mechanism of lysozyme almost illustrates that procedure. Although the classical protein chemistry on lysozyme predated the molecular genetics, the kinetic studies were stimulated by the x-ray crystallography, and the previously unknown mechanism almost leapt from the... 

From genome sequences, a plethora of DNA sequence information is, often publicly, accessible in databases. Pieces of genome sequence have often been annotated, based on sequence similarity to other genes with similar function, to possess a certain function. From the gene sequence, the corresponding protein sequence of a putative enzyme can of course be readily derived so that at this stage the target of the search for a new enzyme is defined. 

The question of whether proteins originate from random sequences of amino acids was addressed in many works. It was demonstrated that protein sequences are not completely random sequences [48]. In particular, the statistical distribution of hydrophobic residues along chains of functional proteins is nonrandom [49]. Furthermore, protein sequences derived from corresponding complete genomes display a distinct multifractal behavior characterized by the so-called generalized Renyi dimensions (instead of a single fractal dimension as in the case of self-similar processes) [50]. It should be kept in mind that sequence correlations in real proteins is a delicate issue which requires a careful analysis. 

Without any doubt, mass spectrometry is now the most efficient way to identify proteins [75-78], The method is based on comparison of the data obtained from the mass spectrometry with those predicted for all the proteins contained in a database. The efficiency of the method results from the development of mass spectrometry into a rapid and sensitive method to analyse peptides and proteins and also from the availability of larger and larger databases. In October 2006, these databases contained more than 2400000 non-redundant sequences. Furthermore, the data obtained from genomic sequences after translation in the six lecture frames also can be used. The databases based on expressed sequence tags (ESTs) are another usable source for search. They are composed of sequences based on cDNA fast sequencing. They are limited to short lengths, about 300 bases, and contain many errors but they correspond to coding sequences. Despite their defects, they are very useful for identification of proteins by mass spectrometry [79]. 

We have seen that, purely using techniques of sequence comparison, the function of about 40% of genes sequenced from genome projects can be inferred from sequence identity or similarity measures or by motif comparison using a variety of techniques. It is known that proteins exhibiting insignificant sequence similarity often adopt similar tertiary structures, which themselves have similar (or at least re-... 

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