ABSTRACT
A functional association is uncovered between the ribosome-associated trigger factor (TF) chaperone and the ClpXP degradation complex. Bioinformatic analyses demonstrate conservation of the close proximity of tig, the gene coding for TF, and genes coding for ClpXP, suggesting a functional interaction. The effect of TF on ClpXP-dependent degradation varies based on the nature of substrate. While degradation of some substrates are slowed down or are unaffected by TF, surprisingly, TF increases the degradation rate of a third class of substrates. These include λ phage replication protein λO, master regulator of stationary phase RpoS, and SsrA-tagged proteins. Globally, TF acts to enhance the degradation of about 2% of newly synthesized proteins. TF is found to interact through multiple sites with ClpX in a highly dynamic fashion to promote protein degradation. This chaperone-protease cooperation constitutes a unique and likely ancestral aspect of cellular protein homeostasis in which TF acts as an adaptor for ClpXP.
Subject(s)
Endopeptidase Clp/metabolism , Molecular Chaperones/metabolism , Proteolysis , Binding Sites , Endopeptidase Clp/chemistry , Escherichia coli/genetics , Escherichia coli Proteins , Gene Deletion , Genome, Bacterial , Magnetic Resonance Spectroscopy , Models, Biological , Models, Molecular , Mutagenesis , Peptides/metabolism , Peptidylprolyl Isomerase , Phylogeny , Protein Binding , Protein Domains , Protein Interaction Mapping , Protein Multimerization , Ribosomes/metabolism , Substrate Specificity , Viral Proteins/metabolismABSTRACT
BACKGROUND: Leukemia is the most common cancer among Canadian children, representing about a third of pediatric cancers in Canada and is responsible for about one-third of pediatric cancer deaths. Understanding the effect of socioeconomic status (SES) on pediatric leukemia incidence provides valuable information for cancer control and interventions in Canada. METHODS: Using a linked data from the Canadian Cancer Registry (CCR), Canadian Census of Population (CCP) and National Household Survey (NHS) we aimed to quantify socioeconomic inequalities in the incidence of pediatric leukemia from 1992 to 2010. We used the concentration index (C) approach to quantify income- and education-related inequalities in the incidence of pediatric leukemia over time. RESULTS: Though there were fluctuations in incidence over the study period, our results showed that the total incidence of pediatric leukemia in Canada was generally consistent from 1992 to 2010. Incidence rate of 47 per 1,000,000 as at 1992 rose to 57 per 1,000,000 in 2010. The estimated values of the C over the study period failed to show any significant association between pediatric leukemia incidence and household income or education status. CONCLUSIONS: Although pediatric leukemia incidence is not rising significantly, it is not reducing significantly either. The incidence of pediatric leukemia showed no significant association with socioeconomic status. Future cancer control interventions should focus more on mitigating risk factors that are independent of socioeconomic status.
Subject(s)
Leukemia/epidemiology , Social Class , Adolescent , Canada/epidemiology , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Risk FactorsABSTRACT
ClpP is a highly conserved serine protease present in most bacterial species and in the mitochondria of mammalian cells. It forms a cylindrical tetradecameric complex arranged into two stacked heptamers. The two heptameric rings of ClpP enclose a roughly spherical proteolytic chamber of about 51 Å in diameter with 14 Ser-His-Asp proteolytic active sites. ClpP typically forms complexes with unfoldase chaperones of the AAA+ superfamily. Chaperones dock on one or both ends of the ClpP double ring cylindrical structure. Dynamics in the ClpP structure is critical for its function. Polypeptides targeted for degradation by ClpP are initially recognized by the AAA+ chaperones. Polypeptides are unfolded by the chaperones and then translocated through the ClpP axial pores, present on both ends of the ClpP cylinder, into the ClpP catalytic chamber. The axial pores of ClpP are gated by dynamic axial loops that restrict or allow substrate entry. As a processive protease, ClpP degrades substrates to generate peptides of about 7-8 residues. Based on structural, biochemical and theoretical studies, the exit of these polypeptides from the proteolytic chamber is proposed to be mediated by the dynamics of the ClpP oligomer. The ClpP cylinder has been found to exist in at least three conformations, extended, compact and compressed, that seem to represent different states of ClpP during its proteolytic functional cycle. In this review, we discuss the link between ClpP dynamics and its activity. We propose that such dynamics also exist in other cylindrical proteases such as HslV and the proteasome.
