Sequence and structure motifs

For the in vitro selection process, the RNA pool containing 10 different sequences and structural motifs is generated by an in vitro transcription reaction. Folding of the RNA molecules is induced by heat denaturation and renaturation at room temperature (26). 

J. Gorodkin, L.J. Heyer, and G.D. Stormo. Finding the most significant common sequence and structure motifs in a set of RNA sequences. Nucleic Acids Res., 25 3724-3732,1997. 

Because of its structural simplicity and instrumental role in protein function, the coiled coil is one of the most investigated protein folding motifs. Native coiled-coil sequences and their mutants have been synthesized and studied. Numerous model coiled-coil peptides have been designed de novo [22]. Although many theoretical questions remain unanswered, much has been learned about the sequence-structure relationship. It is even possible to design and engineer new coiled-coil sequences and structures that have never existed before [23]. 

Grillo, G., Licciulh, F., Liuni, S., Sbisa, E., and Pesole, G. (2003) PatSearch a program for the detection of patterns and structural motifs in nucleotide sequences. Nucleic Acids Res. 31, 3608-3612. 

The fundamental structure of immunoglobulins was first established by Gerald Edelman and Rodney Porter. Each chain is made up of identifiable domains some are constant in sequence and structure from one IgG to the next, others are variable. The constant domains have a characteristic structure known as the immunoglobulin fold, a well-conserved structural motif in the all /3 class of proteins (Chapter 4). There are three of these constant domains in each heavy chain and one in each light chain. The heavy and light chains also have one variable domain each, in which most of the variability in amino acid residue sequence is found. The variable domains associate to create the antigen-binding site (Fig. 5-24). 

Fig. 3. The acidic regions of rgRGS domains. The rgRGS domains consist of a core RGS box, which is homologous in sequence and structure to other RGS domains, a C-terminal extension that helps stabilize the core structure, and an N-terminal acidic region that forms a second binding motif to the a subunit. Amino acids in bold-underline were shown to have contacts with G13a mutations of residues indicated with an arrow could attenuate GAP activity. This acidic region plays a fundamental role in GAP activity, and differences among the RGS-RhoGEFs appear to determine their ability to act as GAPs. See text for details.

The sequence and structural conservations at the P 2, Po> Pi positions define a major TRAF2 binding motif that bears the consensus sequence of px(Q/E)E, in which Pro is shown in lower case because it can be substituted for other medium sized non-charged residues. Most of the binding sequences identified so far for TRAFl, 2, 3, and 5 are consistent with the motif, thereby explaining the recognition of diverse receptor sequences by TRAF2 (Fig. 6). 

When proteins fold into their tertiary structures, there are often subdivisions within the protein, designated as domains, which are characterised by similar features or motifs. A protein domain is a part of the protein sequence and structure that can evolve, function and exist independently of the rest of the protein chain. Many proteins consist of several structural domains. One domain may appear in a variety of evolutionarily related proteins. Domains vary in length from about 25 up to 500 amino acids. The shortest domains, such as zinc fingers , are stabilised by metal ions or disulfide bridges. Domains often form functional units, such as the calcium-binding EF hand domain of calmodulin. As they are self-stable, domains can be swapped by genetic engineering between one protein and another, to make chimera proteins. 

In addition to conventional sequence motifs (Prosite, BLOCKS, PRINTS, etc.), the compilation of structural motifs indicative of specific functions from known structures has been proposed [268]. This should improve even the results obtained with multiple (one-dimensional sequence) patterns exploited in the BLOCKS and PRINTS databases. Recently, the use of models to define approximate structural motifs (sometimes called fuzzy functional forms, FFFs [269]) has been put forward to construct a library of such motifs enhancing the range of applicability of motif searches at the price of reduced sensitivity and specificity. Such approaches are supported by the fact that, often, active sites of proteins necessary for specific functions are much more conserved than the overall protein structure (e.g. bacterial and eukaryotic serine proteases), such that an inexact model could have a partly accurately conserved part responsible for function. As the structural genomics projects produce a more and more comprehensive picture of the structure space with representatives for all major protein folds and with the improved homology search methods linking the related sequences and structures to such representatives, comprehensive libraries of highly discriminative structural motifs are envisionable. 

The other major disadvantage today is that prediction methods do not efficiently exploit the available heterogeneous information on function, motifs, family information, network topology, sequence and structure space... 

Protein sequences and structures contain many recognizable motifs and domains. 

Calmodulin (CaM) is a ubiquitous intracellular protein that mediates more than 100 different biological systems in both calcium-free and -loaded forms. CaM has 148 amino acids and its primary sequence is highly conserved in all cell types. It shares strong sequence and structure homology to TnC, which is involved solely in the Calcium-dependent regulation of skeletal and heart muscle contraction. Yeast (yCaM) is 60% identical in sequence to vertebrate CaMs and contains only three functional sites. Several labs have shown that the prokaryotes have several CaM-like proteins containing two or more authentic EF-hand motifs. 

PeUegrini-Galace, M., Thornton, J.M. Detecting DNA-binding hetix-tum-heUx structural motifs using sequence and structure information. Nucleic Acids Res. 2005,33,2129-40. 

While research has shown that the iron oxyhydroxide cores in animal ferritins have the sole purpose of acting as iron storage sites, phosphate can also be associated with these cores and the levels depend on local conditions. In the case of bacterioferritins the native cores always seem to incorporate phosphate and there is some debate as to whether the molecules also perform the further function of phosphate storage. Interestingly, the cavity of bacterioferritins such as those from Eschirichia coli can also be used as a reaction vessel to lay down a variety of other mineral cores. Studies indicate that while details of the protein sequence and structure can vary, overall ferritin proteins can be regarded as possessing a constant set of structural motifs and it is these which are of particular relevance to coordination chemistry. 

By far the most complex and technically demanding predictive method based on protein sequence data has to do with structure prediction. The importance of being able to adequately and accurately predict structure based on sequence is rooted in the knowledge that, whereas sequence may specify conformation, the same conformation may be specified by multiple sequences. The ideas that structure is conserved to a much greater extent than sequence and that there is a limited number of backbone motifs (Chothia and Lesk, 1986 Chothia, 1992) indicate that similarities between proteins may not necessarily be detected through traditional, sequence-based methods only. Deducing the relationship between sequence and structure is at the root of the protein-folding problem, and current research on the problem has been the focus of several reviews (Bryant and Altschul, 1995 Eisenhaber et al., 1995 Lemer et al., 1995). 

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