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CCRXP: exploring clusters of conserved residues in protein structures.

ABSTRACT: Conserved residues forming tightly packed clusters have been shown to be energy hot spots in both protein-protein and protein-DNA complexes. A number of analyses on these clusters of conserved residues (CCRs) have been reported, all pointing to a crucial role that these clusters play in protein function, especially protein-protein and protein-DNA interactions. However, currently there is no publicly available tool to automatically detect such clusters. Here, we present a web server that takes a coordinate file in PDB format as input and automatically executes all the steps to identify CCRs in protein structures. In addition, it calculates the structural properties of each residue and of the CCRs. We also present statistics to show that CCRs, determined by these procedures, are significantly enriched in 'hot spots' in protein-protein and protein-RNA complexes, which supplements our more detailed similar results on protein-DNA complexes. We expect that CCRXP web server will be useful in studies of protein structures and their interactions and selecting mutagenesis targets. The web server can be accessed at http://ccrxp.netasa.org.

SUBMITTER: Ahmad S

PROVIDER: S-EPMC2896124 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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CCRXP: exploring clusters of conserved residues in protein structures.

Ahmad Shandar S Ahmad Shandar S Keskin Ozlem O Mizuguchi Kenji K Sarai Akinori A Nussinov Ruth R

Nucleic acids research 20100510 Web Server issue

Conserved residues forming tightly packed clusters have been shown to be energy hot spots in both protein-protein and protein-DNA complexes. A number of analyses on these clusters of conserved residues (CCRs) have been reported, all pointing to a crucial role that these clusters play in protein function, especially protein-protein and protein-DNA interactions. However, currently there is no publicly available tool to automatically detect such clusters. Here, we present a web server that takes a ...[more]

PMID: 20457748

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Project description:BackgroundLipocalins are widely distributed in nature and are found in bacteria, plants, arthropoda and vertebra. In hematophagous arthropods, they are implicated in the successful accomplishment of the blood meal, interfering with platelet aggregation, blood coagulation and inflammation and in the transmission of disease parasites such as Trypanosoma cruzi and Borrelia burgdorferi. The pairwise sequence identity is low among this family, often below 30%, despite a well conserved tertiary structure. Under the 30% identity threshold, alignment methods do not correctly assign and align proteins. The only safe way to assign a sequence to that family is by experimental determination. However, these procedures are long and costly and cannot always be applied. A way to circumvent the experimental approach is sequence and structure analyze. To further help in that task, the residues implicated in the stabilisation of the lipocalin fold were determined. This was done by analyzing the conserved interactions for ten lipocalins having a maximum pairwise identity of 28% and various functions.ResultsIt was determined that two hydrophobic clusters of residues are conserved by analysing the ten lipocalin structures and sequences. One cluster is internal to the barrel, involving all strands and the 310 helix. The other is external, involving four strands and the helix lying parallel to the barrel surface. These clusters are also present in RaHBP2, a unusual "outlier" lipocalin from tick Rhipicephalus appendiculatus. This information was used to assess assignment of LIR2 a protein from Ixodes ricinus and to build a 3D model that helps to predict function. FTIR data support the lipocalin fold for this protein.ConclusionBy sequence and structural analyzes, two conserved clusters of hydrophobic residues in interactions have been identified in lipocalins. Since the residues implicated are not conserved for function, they should provide the minimal subset necessary to confer the lipocalin fold. This information has been used to assign LIR2 to lipocalins and to investigate its structure/function relationship. This study could be applied to other protein families with low pairwise similarity, such as the structurally related fatty acid binding proteins or avidins.

Project description:Background: Mechanisms of mRNA fate decisions play an important role in determining if a given mRNA will be translated, stored or degraded upon arrival to cytoplasm. Sbp1 is an important RGG-motif containing protein that is implicated in affecting mRNA decapping and translation. Sbp1 represses translation by binding eIF4G1 through its RGG-motif and activates decapping when overexpressed. In this report we have assessed the genetic interaction of Sbp1 with decapping activators such as Dhh1, Pat1 and Scd6. We have further analyzed the importance of different domains and specific conserved residues of Sbp1 in translation repression activity. Method: Sequence alignment was performed to identify conserved aromatic residues to be mutated. Using site-directed mutagenesis several point mutations and domain deletions was created in Sbp1 expressed under a galactose-inducible promoter. The mutants were tested for their ability to cause growth defect upon over-expression. The ability of Sbp1 to affect over expression mediated growth defect of other decapping activators was tested using growth assay. Live cell imaging was done to study localization of Sbp1 and its RRM-deletion mutants to RNA granules upon glucose starvation. Results: Mutation of several aromatic residues in the RGG-motif and that of the phosphorylation sites in the RRM domain of Sbp1 did not affect the growth defect phenotype. Deletion of another eIF4G1-binding RGG-motif protein Scd6 does not affect the ability of Sbp1 to cause growth defect. Moreover, absence of Sbp1 did not affect the growth defect phenotypes observed upon overexpression of decapping activators Dhh1 and Pat1. Strikingly deletion of both the RRM domains (RRM1 and RRM2) and not the RNP motifs within them compromised the growth defect phenotype. Sbp1 mutant lacking both RRM1 and RRM2 was highly defective in localizing to RNA granules. Conclusion: This study identifies an important role of RRM domains independent of RNP motif in Sbp1 repression activity.

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CCRXP: exploring clusters of conserved residues in protein structures.

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CCRXP: exploring clusters of conserved residues in protein structures.

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