Summary BAliBASE is a database of manually refined multiple sequence alignments categorized by core blocks of conservation sequence length, similarity, and the presence of insertions and N/C-terminal extensions. Availability From http://www-igbmc. u-strasbg.fr/BioInfo/BAliBASE/index.html

BAliBASE: a benchmark alignment database for the evaluation of multiple alignment programs.

This review summarizes the recent discovery of the cupin superfamily (from the Latin term "cupa," a small barrel) of functionally diverse proteins that initially were limited to several higher plant proteins such as seed storage proteins, germin (an oxalate oxidase), germin-like proteins, and auxin-binding protein. Knowledge of the three-dimensional structure of two vicilins, seed proteins with a characteristic beta-barrel core, led to the identification of a small number of conserved residues and thence to the discovery of several microbial proteins which share these key amino acids. In particular, there is a highly conserved pattern of two histidine-containing motifs with a varied intermotif spacing. This cupin signature is found as a central component of many microbial proteins including certain types of phosphomannose isomerase, polyketide synthase, epimerase, and dioxygenase. In addition, the signature has been identified within the N-terminal effector domain in a subgroup of bacterial AraC transcription factors. As well as these single-domain cupins, this survey has identified other classes of two-domain bicupins including bacterial gentisate 1, 2-dioxygenases and 1-hydroxy-2-naphthoate dioxygenases, fungal oxalate decarboxylases, and legume sucrose-binding proteins. Cupin evolution is discussed from the perspective of the structure-function relationships, using data from the genomes of several prokaryotes, especially Bacillus subtilis. Many of these functions involve aspects of sugar metabolism and cell wall synthesis and are concerned with responses to abiotic stress such as heat, desiccation, or starvation. Particular emphasis is also given to the oxalate-degrading enzymes from microbes, their biological significance, and their value in a range of medical and other applications.

Microbial Relatives of the Seed Storage Proteins of Higher Plants: Conservation of Structure and Diversification of Function during Evolution of the Cupin Superfamily

Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

/pdf/cerebral-cavernous-malformations-arise-from-endothelial-gain-330frac5vm.pdf

Cerebral cavernous malformations arise from endothelial gain of MEKK3–KLF2/4 signalling

Dali and HSSP are derived databases organizing protein space in the structurally known regions. We use an automatic structure alignment program (Dali) for the classification of all known 3D structures based on all-against-all comparison of 3D structures in the Protein Data Bank. The HSSP database associates 1D sequences with known 3D structures using a position-weighted dynamic programming method for sequence profile alignment (MaxHom). As a result, the HSSP database not only provides aligned sequence families, but also implies secondary and tertiary structures covering 36% of all sequences in Swiss-Prot. The structure classification by Dali and the sequence families in HSSP can be browsed jointly from a web interface providing a rich network of links between neighbours in fold space, between domains and proteins, and between structures and sequences. In particular, this results in a database of explicit multiple alignments of protein families in the twilight zone of sequence similarity. The organization of protein structures and families provides a map of the currently known regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The databases are available from http://www.embl-ebi.ac.uk/dali/

/pdf/protein-folds-and-families-sequence-and-structure-alignments-4pg98d7tg6.pdf

Protein folds and families: sequence and structure alignments

Evolution of the thyroid hormone-binding protein, transthyretin.

CAMPASS: a database of structurally aligned protein superfamilies

Correct alignment of the sequence of a target protein with those of homologues of known three-dimensional structure is a key step in comparative modeling. Usually an iterative approach that takes account of the local and overall structural features is required. We describe such an approach that exploits databases of structural alignments of homologous proteins (HOMSTRAD, http:/(/)www-cryst.bioc.cam.ac.uk/ approximately homstrad) and protein superfamilies (CAMPASS, http:/(/)www-cryst.bioc.cam.ac.uk/ approximately campass), in which structure-based alignments are analyzed and formatted with the program JOY (http:/(/)www-cryst.bioc.cam.ac.uk/ approximately joy) to reveal conserved local structural features. The databases facilitate the recognition of a family or superfamily, they assist in the selection of useful parent structures, they are helpful in alignment of the target sequences with the parent set, and are useful for deriving relationships that can be used in validating models. In the iterative approach, a model is constructed on the basis of the proposed sequence alignment and this is then reexpressed in the JOY format and realigned with the parent set. This is repeated until the model and sequence alignment is optimized. We examine the case for comparison and use of multiple structures of family members, rather than a single parent structure. We use the targets attempted by our group in CASP3 to assess the value of such procedures.

An iterative structure-assisted approach to sequence alignment and comparative modeling.

This paper reports the availability of a database of protein structural domains (DDBASE), an alignment database of homologous proteins (HOMSTRAD) and a database of structurally aligned superfamilies (CAMPASS) on the World Wide Web (WWW). DDBASE contains information on the organization of structural domains and their boundaries; it includes only one representative domain from each of the homologous families. This database has been derived by identifying the presence of structural domains in proteins on the basis of inter-secondary structural distances using the program DIAL [Sowdhamini & Blundell (1995), Protein Sci. 4, 506–520]. The alignment of proteins in superfamilies has been performed on the basis of the structural features and relationships of individual residues using the program COMPARER [Sali & Blundell (1990), J. Mol. Biol. 212, 403–428]. The alignment databases contain information on the conserved structural features in homologous proteins and those belonging to superfamilies. Available data include the sequence alignments in structure-annotated formats and the provision for viewing superposed structures of proteins using a graphical interface. Such information, which is freely accessible on the WWW, should be of value to crystallographers in the comparison of newly determined protein structures with previously identified protein domains or existing families.

/pdf/protein-three-dimensional-structural-databases-domains-2hmbm59ygk.pdf

Protein three-dimensional structural databases: domains, structurally aligned homologues and superfamilies

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CAMPASS: a database of structurally aligned protein superfamilies

An iterative structure-assisted approach to sequence alignment and comparative modeling.

Protein three-dimensional structural databases: domains, structurally aligned homologues and superfamilies