Protein domains sequencing

Eortunately, a 3D model does not have to be absolutely perfect to be helpful in biology, as demonstrated by the applications listed above. However, the type of question that can be addressed with a particular model does depend on the model s accuracy. At the low end of the accuracy spectrum, there are models that are based on less than 25% sequence identity and have sometimes less than 50% of their atoms within 3.5 A of their correct positions. However, such models still have the correct fold, and even knowing only the fold of a protein is frequently sufficient to predict its approximate biochemical function. More specifically, only nine out of 80 fold families known in 1994 contained proteins (domains) that were not in the same functional class, although 32% of all protein structures belonged to one of the nine superfolds [229]. Models in this low range of accuracy combined with model evaluation can be used for confirming or rejecting a match between remotely related proteins [9,58]. 

Domain, sequence of amino acids in a protein that can be identified as controlling a specific function, that is, recognition of ligands. 

Alike any other G-protein coupled receptors (GPCRs), mGlu receptors have seven transmembrane helices, also known as the heptahelical domain (Fig. 2). As observed for all GPCRs, the intracellular loops 2 and 3 as well as the C-terminal tail are the key determinants for the interaction with and activation of G-proteins. However, sequence similarity analysis as well as specific structural features make these mGlu receptors different from many other... 

Similar residues in the cores of protein structures especially hydrophobic residues at the same positions, are responsible for common folds of homologous proteins. Certain sequence profiles of conserved residue successions have been identified which give rise to a common fold of protein domains. They are organized in the smart database (simple modular architecture research tool) http //smait.embl-heidelberg.de. 

The Src-homology 2 (SH2) domain is a protein domain of roughly 100 amino acids found in many signaling molecules. It binds to phosphorylated tyrosines, in particular peptide sequences on activated receptor tyrosine kinases or docking proteins. By recognizing specific phosphorylated tyrosines, these small domains serve as modules that enable the proteins that contain them to bind to activated receptor tyrosine kinases or other intracellular signaling proteins that have been transiently phosphorylated on tyrosines. 

Proteins derive their powerful and diverse capacity for molecular recognition and catalysis from their ability to fold into defined secondary and tertiary structures and display specific functional groups at precise locations in space. Functional protein domains are typically 50-200 residues in length and utilize a specific sequence of side chains to encode folded structures that have a compact hydrophobic core and a hydrophilic surface. Mimicry of protein structure and function by non-natural ohgomers such as peptoids wiU not only require the synthesis of >50mers with a variety of side chains, but wiU also require these non-natural sequences to adopt, in water, tertiary structures that are rich in secondary structure. 

The mature AroGP protein domain is composed almost entirely of a repeating 14 amino acid protein motif of the sequence FTxYGxxxN(x)4-6 where F and Y are 100% conserved. 

L, loading module DH, dehydratase KS, p-ketosynthase KR, ketoreductase MT methyltransferase PS, pyran synthase DHh and KRh are DH and KR-like sequences, together with the FkbH domain, they are involved in the formation of D-lactate starter unit HMG-CS, hydroxy-methyl-glutaryl CoA synthase. Acyl-carrier-protein domains are shown as small filled balls with chain attached by the thiol group. The box shows the HMG-CS pathway for the formation of exocyclic enoate. 

The sequence for delivery of copper ions to SOD1 passes from the copper transporter (Ctr) by an unknown pathway to the copper chaperone for SOD1 (CCS) and by a studied pathway from CCS to SOD1. The CCS protein has been studied structurally and found to be similar to other copper chaperones such as those discussed above—Atxl and Atoxl (Hahl). Copper chaperone for superoxide dismutase (CCS) differs from other copper metallochaperones in that it folds into three functionally distinct protein domains with the N-terminal end of domain I... 

This chapter begins with an introduction to protein domains, followed by the steps usually attempted to define domains in a protein. The process begins by looking for well-known domains in the sequence using domain family databases. Then other less well-known domains are sought in the sequence using two popular methods, HMMER and PSI-BLAST. 

Protein domains are the common currency of protein structure and function. Protein domains are discrete structural units that fold up to form a compact globular shape. Experiments on protein structure and function have been greatly aided by consideration of the modular nature of proteins. This has allowed very large proteins to be studied. The expression of individual domains has allowed the intractable giant muscle protein titin to be structurally studied (Pfuhl and Pastore, 1995). Protein domains can be found in a variety of contexts, (Fig. 1), in association with a range of unrelated domains and in a variety of orders. Ultimately protein domains are defined at the level of three-dimensional structure however, many protein domains have been described at the level of sequence. The success of sequence-based methods has been demonstrated by numerous confirmations, by elucidation of the three-dimensional structure of the domain. 

New domains and their boundaries have been defined manually from sequence alone for literally hundreds of protein domains. Finding regions of similarity between proteins allows detection of domains. However, defining the exact boundaries of the domain is often a more difficult problem. Certain rules can be used to find the maximum size of a domain from pairwise comparisons of proteins in a related family. 

In sequence comparison, common protein domains such as the tyrosine kinase domain can mask other interesting matches (Sonnhammer and Durbin, 1994). Other weak but interesting matches may be lost in a large list of matches to the common domain. Thus domain databases are a useful way to identify these common domains so that they can be removed or masked in the sequence to allow the detection of weaker or less common domain similarities. 

Fig. 4. Example of output from the seg program (Wootton, 1994). The seg program was run with default parameters on the SWISS-PROT sequence PSPDHUMAN. (A) Tree output format from seg. Lower case sequence on the left is low complexity, whereas the sequence on the right is high complexity. Note that only the regions between residues 13 and 47 and residues 152 and 375 are large enough to contain protein domains. (B) The second output from seg shows the regions of low complexity masked with Xs this sequence is ready for database searching.

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