Domain families folds

In this respect, the CUE domain is not a isolated case. There are a number of other domain families, each of them only defined in the bioinformatical sense, that have significant matches within established UBA or CUE domain regions. Based on this similarity and on secondary-structure predictions, it can be expected that all of those domain types assume the typical UBA-like three-helix bundle fold. However, it is not clear if all of those domains also bind to ubiquitin, or if they have evolved to different binding properties. Many of the UBA-like domain classes are unpublished. Nevertheless, they should be briefly discussed here, as they are a logical extension of the UBA/CUE paradigm. 

Members from the KorB domain family are characterized by the DNA-binding helix-turn-helix motif (a-3 and a-4). Examples of this protein domain family include the well-studied DNA-binding KorB domain protein, the three-dimensional structure of which has been solved with its operator (PDB accession code lr71, DNA/RNA-binding 3-helical bundle fold Fig. 2a). Amino acid residues outside the HTH motif (Thr-211 and Arg-240) determine the sequence-specific DNA binding (35) (Fig. 2a). 

PTPS (6-Pyruvoyl Tetmhydropterin Synthase). 6-Pyruvoyl tetrahy-dropterin synthase catalyzes formation of tetrahydrobiopterin biosynthesis. Tetrahydrobiopterin is a cofactor for several important enzymes, such as aromatic amino acid hydroxylases and nitric oxide synthase (57). H. pylori protein HPAG1 0913 shares homology with members of the protein domain family PTPS. H. pylori protein shares poor sequence identity of 14% with the PTPS profile at an E-value of 10 10 and covers about 95% of the length of the profile. Fold recognition results also confirm the relationship between H. pylori protein and the PTPS protein domain family. A fold recognition algorithm ensures fitness of the H. pylori protein sequence on the three-dimensional structure of PTPS from... 

The main function of the intracellular calcium binding proteins is to modulate cellular events in response to the calcium signal. Analysis of the sequence of many of the intracellular calcium binding proteins has suggested the existence of two distinct families the EF domain family and the annexin fold family. For completeness, we have grouped the remainder of the intracellular calcium binding proteins into a miscellaneous category. 

OLDERADO clusters the structures of proteins derived from MD simulations into subfamilies based on the conformations of loops and the movement of different protein regions. This clustering is used to select the most representative model from the ensemble of target models constructed. NMRCLUST and NMRCORE can be used individually, but by combining their power and comparing their results with a database of experimentally determined protein family folds, OLDERADO provides additional information about the quality of the final protein model(s). We reiterate that OLDERADO does not construct an average structure, but instead it selects the most representative structure from an ensemble of structures. Clusters of conforma-tionally similar models are created, and the core atoms of protein domains are selected automatically without intervention from the modeler. 

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]. 

The thioredoxin domain (see Figure 2.7) has a central (3 sheet surrounded by a helices. The active part of the molecule is a Pa(3 unit comprising p strands 2 and 3 joined by a helix 2. The redox-active disulfide bridge is at the amino end of this a helix and is formed by a Cys-X-X-Cys motif where X is any residue in DsbA, in thioredoxin, and in other members of this family of redox-active proteins. The a-helical domain of DsbA is positioned so that this disulfide bridge is at the center of a relatively extensive hydrophobic protein surface. Since disulfide bonds in proteins are usually buried in a hydrophobic environment, this hydrophobic surface in DsbA could provide an interaction area for exposed hydrophobic patches on partially folded protein substrates. 

The C-terminal domain of phosducin is a five-stranded mixed p sheet with a helices on both sides, similar to the thioredoxin fold of disulfide iso-merase DsbA described in Chapter 6. Despite significant sequence homology to thioredoxin, the phosducin domain, unlike other members of this family. 

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

Death domain (DD) superfamily consists of structurally related homotypic interaction motifs of approximately 90 amino acids. The motifs are organized in six antiparallel amphipathic a-helices, the so-called DD fold. The four members of the super family are the death domain (DD), the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the Pyrin domain. All are important mediators for the assembly of caspase activating complexes. 

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. 

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