Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043346 (xeroderma pigmentosum)
2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Centrins are members of the EF-hand family of calcium-binding proteins, which are highly conserved among eukaryotes. Centrins bind to several cellular targets, through a hydrophobic triad. However, the W(1)xxL(4)xxxL(8) triad in XPC (Xeroderma Pigmentosum Group C protein) is found in the reverse orientation, as in the L(8)xxxL(4)xxW(1) triad in Sfi1 (Suppressor of Fermentation-Induced loss of stress resistance protein 1). As shown by previous NMR studies of human centrin 2 in complex with XPC or Sfi1, the E148 residue of human centrin 2 is in contact with XPC but is pushed away from the triad of Sfi1. We corroborated these findings using site-directed mutagenesis to generate mutations in Scherffelia dubia centrin (SdCen) and by using isothermal titration calorimetry to analyze the binding affinity of these mutants to XPC and Sfi1. We mutated the F109 residue, which is the main residue involved in target binding regardless of triad orientation, and the E144 residue, which was thought to be involved only in XPC binding. The F109L mutation reduced the binding of SdCen to XPC and Sfi1 and the negative effect was greater upon temperature increase. By contrast, the E144A mutation reduced the binding to XPC but had no effect on Sfi1 binding. The F109L-E144A mutation enhanced the negative effect of the two single mutations on XPC binding. Sfi1 proteins from Ostreococcus lucimarinus and Ostreococcus tauri, which belong to the same clade as S. dubia, were also investigated. A comparative analysis shows that the triad residues are more conserved than those in human Sfi1.
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PMID:The E144 residue of Scherffelia dubia centrin discriminates between the DNA repair protein XPC and the centrosomal protein Sfi1. 2437 20

Calmodulin-like protein 19 (CML19) is an Arabidopsis centrin that modulates nucleotide excision repair (NER) by binding to RAD4 protein, the Arabidopsis homolog of human Xeroderma pigmentosum complementation group C protein. Although the necessity of CML19 as a part of the RAD4 plant recognition complex for functional NER is known at a cellular level, little is known at a molecular level. Herein, we used a combination of biophysical and biochemical approaches to investigate the structural and ion and target-peptide binding properties of CML19. We found that CML19 possesses four Ca²⁺-specific binding sites, two of high affinity in the N-terminal domain and two of low affinity in the C-terminal domain. Binding of Ca²⁺ to CML19 increases its alpha-helix content, stabilizes the tertiary structure, and triggers a conformational change, resulting in the exposure of a hydrophobic patch instrumental for target protein recognition. Using bioinformatics tools we identified a CML19-binding site at the C-terminus of RAD4, and through in vitro binding experiments we analyzed the interaction between a 17-mer peptide representing this site and CML19. We found that the peptide shows a high affinity for CML19 in the presence of Ca²⁺ (stoichiometry 1:1) and the interaction primarily involves the C-terminal half of CML19.
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PMID:Binding of calcium and target peptide to calmodulin-like protein CML19, the centrin 2 of Arabidopsis thaliana. 2912 31


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