Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is proposed to obtain effective Lipari-Szabo order parameters and local correlation times for relaxation vectors of protein (13)CO nuclei by carrying out a (13)CO-R(1) auto relaxation experiment, a transverse (13)CO CSA/13CO-13Calpha CSA/dipolar cross correlation and a transverse (13)CO CSA/(13)CO-(15)N CSA/dipolar cross correlation experiment. Given the global rotational correlation time from (15)N relaxation experiments, a new program COMFORD (CO-Modelfree Fitting Of Relaxation Data) is presented to fit the (13)CO data to an effective order parameter S2CO, an effective local correlation time and the orientation of the CSA tensor with respect to the molecular frame. It is shown that the effective S2CO is least sensitive to rotational fluctuations about an imaginary Calpha-Calpha axis and most sensitive to rotational fluctuations about an imaginary axis parallel to the NH bond direction. As such, the Calpha-Calpha information is fully complementary to the (15)N relaxation order parameter, which is least sensitive to fluctuations about the NH axis and most sensitive to fluctuations about the Calpha-Calpha axis. The new paradigm is applied on data of Ca(2+) saturated Calmodulin, and on available literature data for Ubiquitin. Our data indicate that the S2CO order parameters rapport on slower, and sometimes different, motions than the (15)N relaxation order parameters. The CO local correlation times correlate well with the calmodulin's secondary structure.
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PMID:Quantifying Lipari-Szabo modelfree parameters from 13CO NMR relaxation experiments. 1701 80

Mutations in Cockayne syndrome (CS) A and B genes (CSA and CSB) result in a rare genetic disease that affects the development and homeostasis of a wide range of tissues and organs. We previously correlated the degenerative phenotype of patients to the enhanced apoptotic response, exhibited by CS cells, which is associated with the exceptional induction of p53 protein, upon a variety of stress stimuli. Here we showed that the elevated and persistent levels of p53 displayed by CS cells are due to the insufficient ubiquitination of the p53 protein. We further demonstrated that CSA and CSB proteins associate in a unique complex with p53 and Mdm2; this interaction greatly stimulates the ubiquitination of p53 in an Mdm2-dependent manner. Tandem affinity purification and immunoprecipitations combined with mass spectrometry studies indicate that CSA and CSB associate within a Cullin Ring Ubiquitin Ligase complex responsible, under certain circumstances, for p53 ubiquitination. This study identifies CSA and CSB as the key elements of a regulatory mechanism that equilibrate beneficial and detrimental effects of p53 activity upon cellular stress. The deregulation of p53, in absence of either of the CS proteins, can potentially explain the early onset degeneration of tissues and organs observed in CS patients.
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PMID:CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination. 2208 11