Biology subjects

Burns, T. F.

Publications and source records attributed to Burns, T. F..

3 recordsLinked to original sources

bioRxiv2025

Time-Resolved Crystallography Reveals the Mechanisms of GTP hydrolysis for N-RAS and the Oncogenic Mutants G12C, G12V and Q61L

The RAS family of small GTPases are molecular switches that convey downstream signals regulating cell proliferation, differentiation, and apoptosis. The signaling competent GTP-bound RAS transitions to its inactive GDP-bound form through {gamma}-phosphate hydrolysis. Oncogenic RAS mutations hamper GTP hydrolysis and are present in up to 30% of all human cancers. Structural studies of RAS proteins bound to non-hydrolysable GTP analogs have revealed snapshots of the enzyme in its possibly active form. Yet, the mechanism of GTP hydrolysis has not been structurally resolved. To visualize this reaction in real time, we performed time-resolved crystallographic experiments employing a photolabile caged-GTP substrate. Fifty-seven distinctive reaction intermediates were captured during hydrolysis of a live GTP for N-RAS, the oncogenic mutants G12C, G12V and Q61L; and Y32R, a fast hydrolytic mutant. The reaction mechanisms and rates for the native and each of the mutants differed significantly; however, they shared common elements: an initially catalytically-defective open state, which transitions into the closed Michaelis complex state with solvent-assisted O3B-P{gamma} bond lengthening and breaking, followed by the release of the Mg2+ stabilized PO3-/PO4-3 species and unfolding of the switch loops. Given the conserved nature of GTP- and ATP-ases active sites, this structural work lays the basis to understand the universal mechanism of {gamma}-phosphate hydrolysis. Furthermore, search for cryptic binding sites during GTP hydrolysis in G12C, G12V, and Q61L mutants reveals the presence of distinctive state-dependent binding pockets that could be targets for structure-based drug discovery of experimentally resolved intermediates states.

cancer biology↗

bioRxiv2021

Multiscale and extended retrieval of associative memory structures in a cortical model of local-global inhibition balance

Inhibitory neurons take on many forms and functions. How this diversity contributes to memory function is not completely known. Previous formal studies indicate inhibition differentiated by local and global connectivity in associative memory networks functions to rescale the level of retrieval of excitatory assemblies. However, such studies lack biological details such as a distinction between types of neurons (excitatory and inhibitory), unrealistic connection schemas, and non-sparse assemblies. In this study, we present a rate-based cortical model where neurons are distinguished (as excitatory, local inhibitory, or global inhibitory), connected more realistically, and where memory items correspond to sparse excitatory assemblies. We use this model to study how local-global inhibition balance can alter memory retrieval in associative memory structures, including naturalistic and artificial structures. Experimental studies have reported inhibitory neurons and their sub-types uniquely respond to specific stimuli and can form sophisticated, joint excitatory-inhibitory assemblies. Our model suggests such joint assemblies, as well as a distribution and rebalancing of overall inhibition between two inhibitory sub-populations - one connected to excitatory assemblies locally and the other connected globally - can quadruple the range of retrieval across related memories. We identify a possible functional role for local-global inhibitory balance to, in the context of choice or preference of relationships, permit and maintain a broader range of memory items when local inhibition is dominant and conversely consolidate and strengthen a smaller range of memory items when global inhibition is dominant. This model therefore highlights a biologically-plausible and behaviourally-useful function of inhibitory diversity in memory.

neuroscience↗

bioRxiv2016

A mathematical approach to correlating objective spectro-temporal features of environmental sounds with their subjective perceptions.

Many studies on the subjective perception of non-linguistic sounds have focused on only a single percept, e.g. pleasantness. In the present study, we have examined three different perception-related factors to also allow us to look at any inter-relationships between them that could be related to objective features. Objective features of the NLSs in this database were calculated and subjective perceptions were recorded from participants. These two elements - objective features and subjective perceptions - were then mapped together using various statistical and mathematical techniques. So as to ground our results in a meaningful context, we chose to map a set of objective features to human percepts which had been used in previous studies of NLS perception, but which had not yet been related back to objective features or combinations thereof.

neuroscience↗