Biology subjects

Orr, C.

Publications and source records attributed to Orr, C..

3 recordsLinked to original sources

bioRxiv2025

Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis

The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared to patients with hotspot dominant negative loss of function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through wild-type p53 activity at the mitochondria. These results indicate that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans. Statement of SignificanceInherited TP53 variants cause Li-Fraumeni Syndrome (LFS), which has significant phenotypic heterogeneity in lifetime cancer risk. Our study shows that retention of transcription-independent p53 functions, despite loss of p53 transactivation activity, results in a reduced penetrance phenotype. Classification of TP53 variants should incorporate assays of transcriptional and non-transcriptional functions.

cancer biology↗

bioRxiv2022

Light activation of Orange Carotenoid Protein reveals initial C8'-C7' double bond trans/cis photoisomerization

Orange Carotenoid protein (OCP) is the only known photoreceptor which uses carotenoid for its activation. It is found exclusively in cyanobacteria, where it functions to control light-harvesting of the photosynthetic machinery. However, the photochemical reactions and structural dynamics of this unique photosensing process are not yet resolved. We present time-resolved crystal structures at second-to-minute delays under bright illumination, capturing the early photoproduct and structures of the subsequent reaction intermediates. The first stable photoproduct shows concerted isomerization of C9-C8 and C7-C6 single bonds in the bicycle-pedal (BP) manner and structural changes in the N-terminal domain with minute timescale kinetics. These are followed by a thermally-driven recovery of the BP isomer to the dark state carotenoid configuration. Structural changes propagate to the C-terminal domain, resulting, at later time, in the H-bond rupture of the carotenoid keto group with protein residues. The isomerization and its transient nature are confirmed in OCP crystals and solution by FTIR and UV/Vis spectroscopy. This study reveals the single bond isomerization of the carotenoid in the BP manner and subsequent thermal structural reactions as the basis of OCP photoreception. Understanding and potentially controlling the OCP dynamics offers the prospect of novel applications in biomass engineering as well as in optogenetics and bioimaging.

biophysics↗

bioRxiv2020

The ABCD Stop Signal Data: Response to Bissett et al.

This paper responds to a recent critique by Bissett and colleagues (Bissett et al., eLife, In Press) of the fMRI Stop task being used in the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study(R)). The critique focuses primarily on a design feature of the task that the authors contend lead to a violation of race model assumptions (i.e., that the Go and Stop processes are fully independent) which are relevant to the calculation of the Stop Signal Reaction Time, a measure of the inhibition process. Bissett and colleagues also raise a number of secondary concerns. In this response we note that satisfying race model assumptions is a pernicious challenge for Stop task designs but also that the race model is quite robust against violations of its assumptions. Most importantly, while Bissett et al. raise conceptual concerns with the task we focus here on analyses of both the performance and the neuroimaging data and we conclude that the concerns appear to have minimal impact on the neuroimaging data (the validity of which do not rely on race model assumptions) and have far less of an impact on the performance data than the critique suggests. We note that Bissett et al. did not apply any performance-based exclusions to the data they analyzed, that a number of the trial coding errors that they flagged were already identified and corrected in the ABCD annual data releases, that a number of the secondary concerns reflect sensible design decisions and, indeed, that their own computational modeling of the ABCD Stop task suggests the problems they identify have just a modest impact on the rank ordering of individual differences in subject performance. In this paper, we list some adjustments that have been made to the task and some new flags that are now added to the annual, curated data releases. We stress that the ABCD data are fully available to the scientific community who are empowered to apply whatever inclusion and exclusion criteria they deem appropriate for their analyses and we conclude that the ABCD Stop task yields valuable data that researchers can use to track adolescent neurodevelopment.

neuroscience↗