Protein structural domain

Some of the best understood polyvalent interactions are found in immune and host defense systems as well as ligand-receptor activation. An example is the use of a polyvalent immunogen based on a synthetic peptide to elicit immune responses. The subsequent production of site-specific antibodies can then be employed to confirm the identity of proteins derived from recombinant DNA, to explore biosynthetic pathways, to define precursor-product relationships (e.g., proenzyme and preproenzyme), and to determine protein structural domains.19 ... 

The development of chemoselective reactions to give a native peptide bond at the site of hgation allows the synthesis of proteins with little or no modification to the covalent structure. A native structure at the ligation site is often desirable in the middle of protein structural domains (amino acid 60-120). The challenge of this approach is to form an amide bond chemoselectively in the presence of free amine side chains (Lys) and carboxylate side chains (Glu/Asp). Ideally, no protecting groups should be used for any of the amino acid side chains as they limit peptide solubility and require additional deprotection steps that can severely reduce the yield and convenience of the synthesis. 

R. Sowdhamini, S. D. Rufino, T. L. Blundell. A database of globular protein structural domains clustering of representative family members into similar folds. Fold. Des. 1996, 1, 209-220. 

George, R. A., and J. Heringa. 2002. SnapDRAGON A method to delineated protein structural domains from sequence data. J Mol Biol 316 839-51. 

R 141 R.A. George, J. Kleinjung and J. Heringa, Predicting Protein Structural Domain Boundaries from Sequence Data , p. 1... 

As more protein structures became available it was observed that some contained more that one distinct region, with each region often having a separate function. Each of these region is usually known as a domain, a domain being defined as a polypeptide chain that can folc independently into a stable three-dimensional structure. 

Although comparative modeling is the most accurate modeling approach, it is limited by its absolute need for a related template structure. For more than half of the proteins and two-thirds of domains, a suitable template structure cannot be detected or is not yet known [9,11]. In those cases where no useful template is available, the ab initio methods are the only alternative. These methods are currently limited to small proteins and at best result only in coarse models with an RMSD error for the atoms that is greater than 4 A. However, one of the most impressive recent improvements in the field of protein structure modeling has occurred in ab initio prediction [155-157]. 

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]. 

Protein folding remains a problem because there are 20 different amino acids tbat can be combined into many more different proteins tban there are atoms in the known universe. In addition there is a vast number of ways in which similar structural domains can be generated in proteins by different amino acid sequences. By contrast, the structure of DNA, made up of only four different nucleotide building blocks that occur in two pairs, is relatively simple, regular, and predictable. 

Several motifs usually combine to form compact globular structures, which are called domains. In this book we will use the term tertiary structure as a common term both for the way motifs are arranged into domain structures and for the way a single polypeptide chain folds into one or several domains. In all cases examined so far it has been found that if there is significant amino acid sequence homology in two domains in different proteins, these domains have similar tertiary structures. 

The fundamental unit of tertiary structure is the domain. A domain is defined as a polypeptide chain or a part of a polypeptide chain that can fold independently into a stable tertiary structure. Domains are also units of function. Often, the different domains of a protein are associated with different functions. For example, in the lambda repressor protein, discussed in Chapter 8, one domain at the N-terminus of the polypeptide chain binds DNA, while a second domain at the C-terminus contains a site necessary for the dimerization of two polypeptide chains to form the dimeric repressor molecule. 

On the basis of simple considerations of connected motifs, Michael Leviff and Cyrus Chothia of the MRC Laboratory of Molecular Biology derived a taxonomy of protein structures and have classified domain structures into three main groups a domains, p domains, and a/p domains. In ct structures the core is built up exclusively from a helices (see Figure 2.9) in p structures the core comprises antiparallel p sheets and are usually two P sheets packed... 

Jurnak, E, et al. Parallel p domains a new fold in protein structures. Curr. Opin. Struct. Biol. 4 802-806, 1994. 

His 57 and Ser 195 are within loop 3-4 of domains 1 and 2, respectively. The third residue in the catalytic triad. Asp 102, is within loop 5-6 of domain 1. The rest of the active site is formed by two loop regions (3-4 and 5-6) of domain 2. As in so many other protein structures described previously, the barrels apparently provide a stable scaffold to position a few loop regions that constitute the essential features of the active site. 

Now that many thousands of proteins have been sequenced (more than 100,000 sequences are known), it has become obvious that certain protein sequences that give rise to distinct structural domains are used over and over again in modular fashion. These protein modules may occur in a wide variety of pro-... 

The immunoglobulin structure in Figure 6.45 represents the confluence of all the details of protein structure that have been thus far discussed. As for all proteins, the primary structure determines other aspects of structure. There are numerous elements of secondary structure, including /3-sheets and tight turns. The tertiary structure consists of 12 distinct domains, and the protein adopts a heterotetrameric quaternary structure. To make matters more interesting, both intrasubunit and intersubunit disulfide linkages act to stabilize the discrete domains and to stabilize the tetramer itself. 

Adaptor Proteins. Figure 1 Adaptor protein domains. A scheme of the domain structures of some well-characterized adaptor proteins is shown. Descriptions of domain characteristics are in main text except C2, binds to phospholipids GTPase activating protein (GAP) domain, inactivates small GTPases such as Ras Hect domain, enzymatic domain of ubiquitin ligases and GUK domain, guanylate kinase domain. For clarity, not all domains contained within these proteins are shown. 

Detailed protein structures have been reported for BPI and CETP. Given the aforementioned similarities within this gene family, these protein structures serve as a likely model for the protein structure of PLTP. CETP and BPI are elongated molecules, shaped like a boomerang. There are two domains with similar folds, and a central beta-sheet domain between these two domains. The molecules contain two lipid-binding sites, one in each domain near the interface of the barrels and the central beta-sheet. 

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. 

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