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The anaphase-promoting complex or cyclosome (APC/C) is a large E3 RING-cullin ubiquitin ligase composed of between 14 and 15 individual proteins. A striking feature of the APC/C is that only four proteins are involved in directly recognizing target proteins and catalyzing the assembly of a polyubiquitin chain. All other subunits, which account for >80% of the mass of the APC/C, provide scaffolding functions. A major proportion of these scaffolding subunits are structurally related. In metazoans, there are four canonical tetratricopeptide repeat (TPR) proteins that form homo-dimers (Apc3/Cdc27, Apc6/Cdc16, Apc7 and Apc8/Cdc23). Here, we describe the crystal structure of the N-terminal homo-dimerization domain of Schizosaccharomyces pombe Cdc23 (Cdc23(Nterm)). Cdc23(Nterm) is composed of seven contiguous TPR motifs that self-associate through a related mechanism to those of Cdc16 and Cdc27. Using the Cdc23(Nterm) structure, we generated a model of full-length Cdc23. The resultant "V"-shaped molecule docks into the Cdc23-assigned density of the human APC/C structure determined using negative stain electron microscopy (EM). Based on sequence conservation, we propose that Apc7 forms a homo-dimeric structure equivalent to those of Cdc16, Cdc23 and Cdc27. The model is consistent with the Apc7-assigned density of the human APC/C EM structure. The four canonical homo-dimeric TPR proteins of human APC/C stack in parallel on one side of the complex. Remarkably, the uniform relative packing of neighboring TPR proteins generates a novel left-handed suprahelical TPR assembly. This finding has implications for understanding the assembly of other TPR-containing multimeric complexes.
Pubmed ID: 23583778 RIS Download
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A platform that integrates a great variety of tools for protein sequence analysis. Many tools are developed in-house, and serveral public tools are offered with extended functionality. Most frequently used tools HHpred Sensitive protein homology detection and structure prediction by HMM-HMM-comparison. Starting from a query sequence, HHpred builds a multiple sequence alignment using HHblits and turns it into a profile HMM. This is then compared it with a database of HMMs representing proteins with known structure (e.g. PDB, SCOP) or annotated protein families (e.g. PFAM, SMART, CDD, COGs, KOGs). The output is a list of closest homologs with alignments. HHpred can also build 3d homology models using the identified templates in the PDB database. It can optimize template picking and query-template alignments for homology modeling. The HHblits software is part of the open source package HHsuite. HHblits Remote homology detection method based on iterative HMM-HMM comparison. HHblits can build high-quality MSAs starting from single sequences or from MSAs. It transforms these into a query HMM and iteratively searches through uniprot20 or nr20 databases by adding significantly similar sequences from the previous search to the updated query HMM for the next search iteration. Compared to PSI-BLAST, HHblits is faster, up to twice as sensitive and produces more accurate alignments. The HHblits software is part of the open source package HHsuite. Quick2d Quick2D gives you an overview of secondary structure features like alpha-helices, extended beta-sheets, coiled coils, transmembrane helices and disorder regions. Predictions by PSIPRED, JNET, Prof(Rost), Prof(Ouali), Coils, MEMSAT2, HMMTOP, DISOPRED2 and VSL2. Modeller A Program for Comparative Protein Structure Modelling by Satisfaction of Spatial Restraints. Coils/PCoils This server compares a single sequence (COILS) or a sequence alignment (PCOILS) to a database of known coiled-coils and derives a similarity score. The program then calculates the probability that the sequence will adopt a coiled-coil conformation. PSI-Blast Search with an amino acid sequence against protein databases for locally similar sequences. Similar to ProteinBLAST but more sensitive. PSI-BLAST first performs a BLAST search and builds an alignment from the best local hits. This alignment is then used as a query for the next round of search. After each successive round the search alignment is updated.
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