Biomedical subjects

Charlotte M Deane

Publications and source records attributed to Charlotte M Deane.

6 recordsLinked to original sources

PubMed2006

Modelling sequential protein folding under kinetic control.

MOTIVATION: This study presents a novel investigation of the effect of kinetic control on cotranslational protein folding. We demonstrate the effect using simple HP lattice models and show that the cotranslational folding of proteins under kinetic control has a significant impact on the final conformation. Differences arise if nature is not capable of pushing a partially folded protein back over a large energy barrier. For this reason we argue that such constraints should be incorporated into structure prediction techniques. We introduce a finite surmountable energy barrier which allows partially formed chains to partly unfold, and permits us to enumerate exhaustively all energy pathways. RESULTS: We compare the ground states obtained sequentially with the global ground states of designing sequences (those with a unique global ground state). We find that the sequential ground states become less numerous and more compact as the surmountable energy barrier increases. We also introduce a probabilistic model to describe the distribution of final folds and allow partial settling to the Boltzmann distribution of states at each stage. As a result, conformations with the highest probability of final occurrence are not necessarily the ones of lowest energy. AVAILABILITY: Software available on request.

Amino Acid Sequence↗

PubMed2006

Protein protein interactions, evolutionary rate, abundance and age.

BACKGROUND: Does a relationship exist between a protein's evolutionary rate and its number of interactions? This relationship has been put forward many times, based on a biological premise that a highly interacting protein will be more restricted in its sequence changes. However, to date several studies have voiced conflicting views on the presence or absence of such a relationship. RESULTS: Here we perform a large scale study over multiple data sets in order to demonstrate that the major reason for conflict between previous studies is the use of different but overlapping datasets. We show that lack of correlation, between evolutionary rate and number of interactions in a data set is related to the error rate. We also demonstrate that the correlation is not an artifact of the underlying distributions of evolutionary distance and interactions and is therefore likely to be biologically relevant. Further to this, we consider the claim that the dependence is due to gene expression levels and find some supporting evidence. A strong and positive correlation between the number of interactions and the age of a protein is also observed and we show this relationship is independent of expression levels. CONCLUSION: A correlation between number of interactions and evolutionary rate is observed but is dependent on the accuracy of the dataset being used. However it appears that the number of interactions a protein participates in depends more on the age of the protein than the rate at which it changes.

Aging↗

PubMed2005

Fold usage on genomes and protein fold evolution.

We review fold usage on completed genomes to explore protein structure evolution. The patterns of presence or absence of folds on genomes gives us insights into the relationships between folds, the age of different folds and how we have arrived at the set of folds we see today. We examine the relationships between different measures which describe protein fold usage, such as the number of copies of a fold per genome, the number of families per fold, and the number of genomes a fold occurs on. We obtained these measures of fold usage by searching for the structural domains on 157 completed genome sequences from all three kingdoms of life. In our comparisons of these measures we found that bacteria have relatively more distinct folds on their genomes than archaea. Eukaryotes were found to have many more copies of a fold on their genomes. If we separate out the different fold classes, the alpha/beta class has relatively fewer distinct folds on large genomes, more copies of a fold on bacteria and more folds occurring in all three kingdoms simultaneously. These results possibly indicate that most alpha/beta folds originated earlier than other folds. The expected power law distribution is observed for copies of a fold per genome and we found a similar distribution for the number of families per fold. However, a more complicated distribution appears for fold occurrence across genomes, which strongly depends on fold class and kingdom. We also show that there is not a clear relationship between the three measures of fold usage. A fold which occurs on many genomes does not necessarily have many copies on each genome. Similarly, folds with many copies do not necessarily have many families or vice versa.

Archaeal Proteins↗

PubMed2005

How old is your fold?

MOTIVATION: At present there exists no age estimate for the different protein structures found in nature. It has become clear from occurrence studies that different folds arose at different points in evolutionary time. An estimation of the age of different folds would be a starting point for many investigations into protein structure evolution: how we arrived at the set of folds we see today. It would also be a powerful tool in protein structure classification allowing us to reassess the available hierarchical methods and perhaps suggest improvements. RESULTS: We have created the first relative age estimation technique for protein folds. Our method is based on constructing parsimonious scenarios, which can describe occurrence patterns in a phylogeny of species. The ages presented are shown to be robust to the different trees or data types used for their generation. They show correlations with other previously used protein age estimators, but appear to be far more discriminating than any previously suggested technique. The age estimates given are not absolutes but they already offer intriguing insights, like the very different age patterns of alpha/beta folds compared with small folds. The alpha/beta folds appear on average to be far older than their small fold counterparts. AVAILABILITY: Example trees and additional material are available at http://www.stats.ox.ac.uk/~abeln/foldage SUPPLEMENTARY INFORMATION: http://www.stats.ox.ac.uk/~abeln/foldage.

Algorithms↗

PubMed2004

Solution structure and dynamics of a prototypical chordin-like cysteine-rich repeat (von Willebrand Factor type C module) from collagen IIA.

Chordin-like cysteine-rich (CR) repeats (also referred to as von Willebrand factor type C (VWC) modules) have been identified in approximately 200 extracellular matrix proteins. These repeats, named on the basis of amino acid conservation of 10 cysteine residues, have been shown to bind members of the transforming growth factor-beta (TGF-beta) superfamily and are proposed to regulate growth factor signaling. Here we describe the intramolecular disulfide bonding, solution structure, and dynamics of a prototypical chordin-like CR repeat from procollagen IIA (CR(ColIIA)), which has been previously shown to bind TGF-beta1 and bone morphogenetic protein-2. The CR(ColIIA) structure manifests a two sub-domain architecture tethered by a flexible linkage. Initial structures were calculated using RosettaNMR, a de novo prediction method, and final structure calculations were performed using CANDID within CYANA. The N-terminal region contains mainly beta-sheet and the C-terminal region is more irregular with the fold constrained by disulfide bonds. Mobility between the N- and C-terminal sub-domains on a fast timescale was confirmed using NMR relaxation measurements. We speculate that the mobility between the two sub-domains may decrease upon ligand binding. Structure and sequence comparisons have revealed an evolutionary relationship between the N-terminal sub-domain of the CR module and the fibronectin type 1 domain, suggesting that these domains share a common ancestry. Based on the previously reported mapping of fibronectin binding sites for vascular endothelial growth factor to regions containing fibronectin type 1 domains, we discuss the possibility that this structural homology might also have functional relevance.

Algorithms↗

PubMed2002

Protein interactions: two methods for assessment of the reliability of high throughput observations.

High throughput methods for detecting protein interactions require assessment of their accuracy. We present two forms of computational assessment. The first method is the expression profile reliability (EPR) index. The EPR index estimates the biologically relevant fraction of protein interactions detected in a high throughput screen. It does so by comparing the RNA expression profiles for the proteins whose interactions are found in the screen with expression profiles for known interacting and non-interacting pairs of proteins. The second form of assessment is the paralogous verification method (PVM). This method judges an interaction likely if the putatively interacting pair has paralogs that also interact. In contrast to the EPR index, which evaluates datasets of interactions, PVM scores individual interactions. On a test set, PVM identifies correctly 40% of true interactions with a false positive rate of approximately 1%. EPR and PVM were applied to the Database of Interacting Proteins (DIP), a large and diverse collection of protein-protein interactions that contains over 8000 Saccharomyces cerevisiae pairwise protein interactions. Using these two methods, we estimate that approximately 50% of them are reliable, and with the aid of PVM we identify confidently 3003 of them. Web servers for both the PVM and EPR methods are available on the DIP website (dip.doe-mbi.ucla.edu/Services.cgi).

Algorithms↗