Fold families

Holm L and C Sander 1994. The FSSP Database of Structurally Aligned Protein Fold Families. Ni Acids Research 22 3600-3609. 

Orengo C A, T P Flores W R Taylor and J M Thornton 1993. Identification and Oassificalion of Prc Fold Families. Protein Engineering 6 485-500. 

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 primary and tertiary structures of the cholinesterases are known. The primary structures of the cholinesterases initially defined a large and functionally eclectic superfamily of proteins, the a,P hydrolase fold family, that function not only catalytically as hydrolases but also as surface adhesion molecules forming heterologous cell contacts, as seen in the structurally related proteins... 

The six well-conserved half cystine residues in a protein exhibiting the same pattern of cysteine spacing along with significant sequence similarity suggest that the protein may belong to the same structural (folding) family as PBPs and, consequently, infer that it may function in the same fashion. The assumption that such a protein is involved in olfaction, however, would be compromised if the protein was identified in non-olfactory tissues. Even if a non-olfactory protein has the same function as an OBP (carrier, for example), one has to keep in mind... 

Bacillus subtilis /zNB esterase is a member of the a./(3 hydrolase fold family (Moore and Arnold, 1996 Ollis et al., 1992). The canonical a/j3 hydrolase fold consists of a mostly parallel eight-stranded [3 sheet surrounded on both sides by a helices (Nardini and Dijkstra, 1999). p B esterase contains 489 amino acids arranged in a central thirteen-stranded f3 sheet that is surrounded by fifteen a helices (Fig. 12, see color insert). Similar to the structure of acetylcholine esterase (Sussman et al., 1991), a large fraction of the pSB esterase structure has no defined secondary structure (52% random coil, 33% a helix, and 14% /3 sheet). This high degree of random coil structure is allowed in the a/(3 hydrolase fold, where large insertions in loops were found to be tolerated while still maintaining catalytic activity (Nardini and Dijkstra, 1999). 

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. 

The exact function of the annexin fold family is at present unclear. All of these proteins appear to show calcium-dependent binding to phosphatidylethanolamine or phosphatidylinositol liposomes. In addition, they can promote fusion of liposomes, and because of this property, it has been suggested that these proteins might mediate calcium dependent exocytosis. P36 and p35 have also been shown to bind to F-actin and spectrin [65,66]. Recently, Khanna et al. [70] have reported a procedure for the simultaneous purification of p35, p36 oligomer and p36 monomer from bovine lung, and identified all three proteins as substrates of protein kinase C. Furthermore, the work of Huang et al. [86] and Khanna et al. [69] has suggested that all three proteins are inhibitors of phospholipase A2. Further experiments will be required to clarify the function of these proteins. 

The GT-B fold family includes most prokaryotic enzymes that produce secondary metabolites, like the antibiotics streptomycin, oleandomycin (Fig. 1) and vancomycin, and important bacterial cell wall precursors. It is also predicted to contain the vitally important 0-GlcNAc transferase that modifies many nuclear and cytoplasmic proteins and influences gene transcription. The first glycosyltransferase structure reported in 1994 was for the GT-B fold enzyme, P-glucosyltransferase (BGT) from bacteriophage T4 (22). This enzyme attaches glucose to modified... 

In addition to the variations of the GT-A and GT-B fold described above for sialyltransferases (7, 8) and fucosyltrans-ferases (17), a distinct GT-C fold family has been predicted for GTs that use lipid linked donors. The crystal structures of the GT domain of the peptidoglycan glycosyltransferase from Staphylococcus aureus (18) (Fig. 3f) and Aquifex aeolicus, (26) show structural similarity to the bacteriophage k-lysozyme. These novel structures demonstrate the possibility of additional folds. 

The following proteins were chosen for multiple sequence alignment T. califomica acetylcholinesterase, Xanthobacter autotrophicus haloalkane dehalogenase, G. candidum lipase and wheat serine carboxypeptidase. This set was selected because they are all members of the o/fi hydrolase fold family (Ollis et al, 1992). This family of proteins, which is believed to have evolved by... 

Table L Pairwise Sequence Identities of JHE to Proteins of the a/p Hydrolase Fold Family.

The first observation of this kind of analysis is that for all types of measures utilized the behavior of predictive methods varies significantly according to the protein fold family. This can be relevant in pointing out what method performs better for the prediction of a determined structural element depending on the protein class. Conversely, it also is possible to diagnose critical points where the algorithms fail. 

The crystal structure of the HGL, expressed in baculovirus/insect ci ll system was obtained at 3 A resolution [35]. This structure was the first to be resolved within the acidic lipases family. HGL is a globular protein that exhibits the a/ hydrolase fold (Fig. 9.2). The final model contains residues 9 to 53 and 57 to 379, six sugar residues located on the four potential N-glycosylation sites and a disulfide bridge Cys 227-Cys 236, whereas Cys 244 is free (Fig. 9.2). In hpases, as weU as in serine proteases [36], the catalytic machinery consists of a triad and an oxyariiori hole. In HGL, the nucleophilic serine (Ser 153) belonging to the usual consensus sequence G-X-S-X-G is located at the cormection between an a hehx and a f strand has an e conformation, which are characteristic features of all enzymes within the alP hydrolase fold family ]21]. His 353 and Asp 324 are the other two residues... 

Hohn, L. and Sander, C., The FSSP database of structurally aligned protein fold families. Nucleic Acids Res., 24, 206, 1996. 

Touzet, H. and Perriquet, O. (2004) CARNAC folding families of non coding RNAs. Nucleic Acids Res. 142, W142-W145. 

The ESTHER database, maintained at the INRA-ENSAM in Montpellier, follows a similar concept but focuses on the a/fi fold family of esterases/lipases 59. ... 

Several membrane-bound and soluble epoxide hydrolases from mammalian origin have been purified and (at least partially) sequenced. Some of them have also been cloned and overexpressed, which is the case for the soluble EH from rat liver which has been overexpressed in Escherichia cob 54, 55. This enzyme (as well as its microsomal analog) was shown to share an amino acid sequence similarity to a region around the active center of a bacterial haloalkane dehalogenase 56, an enzyme with known three-dimensional structure that belongs to the a/(3-hydrolase fold-family 571. Rat soluble EH forms a dimer from two complete structural monomeric units, both possessing a distinct active site. The EH activity is known to be located close to the C-terminal unit, while the function of the N-terminal unit remains unknown 581. 

However, as discussed above in Section 7.12.2.1.2, the MenH protein has been unequivocally demonstrated to carry out the conversion of the newly discovered intermediate SEPHCHC to SHCHC and has been christened as SHCHC synthase. Thus, the enzyme responsible for the conversion of DHNA-CoA to DH2NA still remains to be identified. In this connection, it is worth mentioning that in the cyanobacterium Synechocystis sp. a DHNA-CoA thioesterase belonging to the hotdog-fold family has been recently shown to be essential for K biosynthesis. "... 

From the practical viewpoint, as noted by Durovic (1982), the family reflections of the nine-fold family structure (S rows) are common to all members of a family and are thus not useful for the purpose of distinguishing individual polytypes. D rows instead are characteristic of all members of a subfamily (A or B, in case of micas), permit to distinguish the kind of polytype (subfamily A, subfamily B or mixed-rotation). 

S rows (family reflections of the nine-fold family structure) one reflection out of N always occurs, with presence criterion lc = 0(mod N). 

In mixed-rotation polytypes, the family reflections are only those of the nine-fold family structure and appear along S rows. D rows convey important information, because the different number of reflections along the rows, or their diffuseness, unambiguously reveals the mixed-rotation character of the polytype. 

---