Biology subjects

Deutsch, C.

Publications and source records attributed to Deutsch, C..

4 recordsLinked to original sources

bioRxiv2025

Early-stage determinants of T1-S1 conformations in Kv1.3 channels

Early-stage biogenesis of voltage-gated potassium channels (Kv) remains remarkably understudied yet is key to defining co- and post-translational acquisition of Kv secondary, tertiary, and quaternary conformations. Thus, we have studied nascent folding events and their determinants in Kv1.3, a tetrameric ion channel highly expressed in nerve and immune cells. We explore how folding of T1, an intersubunit recognition domain that ensures correct isoform assembly, is modulated by molecular determinants in the Kv subunit. Specifically, we focus on the T1-S1 linker and its highly conserved C-terminal sequence, S0. Using pegylation, a mass-tagging strategy, inter- and intrasubunit crosslinking, we define the molecular determinants of T1-S1 linker accessibility and location. Our findings show that i) dynamic protein-lipid and protein-protein linker interfaces exist, ii) the presence of a T1 domain and its conformation (monomer versus tetramer) impact linker properties, iii) helical formation of S0 occurs in early biogenic stages and does not require the presence of membranes, iv) a core recognition domain (T2) increases T1 dimerization efficiency and promotes tetramer formation, and v) as few as 12 native linker residues enable T1 tetramerization. These findings differ from canonical models and suggest that domain plasticity for Kv1.3 contributes to biogenesis and may underlie domain-domain communication in Kv function.

physiology↗

bioRxiv2021

Ribosome elongation kinetics of consecutively charged residues are coupled to electrostatic force

The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multi-scale simulations, that positively charged residues generate large forces that pull the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but opposite direction. And that these conformational changes, respectively, raise and lower the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting a proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome-nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation, and provide a framework for interpreting experimental results on translation speed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/455055v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14714eeorg.highwire.dtl.DTLVardef@1af3ad7org.highwire.dtl.DTLVardef@1402740org.highwire.dtl.DTLVardef@d11c04_HPS_FORMAT_FIGEXP M_FIG C_FIG For table of contents use only.

biophysics↗

bioRxiv2021

Biochemical Barriers on the Path to Ocean Anoxia?

The kinetics of microbial respiration suggest that, if excess organic matter is present, oxygen should fall to nanomolar levels, in the range of the Michaelis-Menten constants (Km). Yet even in many biologically productive coastal regions, lowest observed O2 concentrations often remain several orders of magnitude higher than respiratory Km values. We propose the Hypoxic Barrier Hypothesis (HBH) to explain this apparent discrepancy. The HBH postulates that oxidative enzymes involved in organic matter catabolism are kinetically limited by O2 at concentrations far higher than the thresholds for respiration. We found support for the HBH in a meta-analysis of 1137 O2 Km values reported in the literature: the median value for terminal respiratory oxidases was 350 nM, but for other oxidase types the median value was 67 M. The HBH directs our attention to the kinetic properties of an important class of oxygen-dependent reactions that could help explain the trajectories of ocean ecosystems experiencing O2 stress. IMPORTANCEDeclining ocean oxygen associated with global warming and climate change is impacting marine ecosystems across scales from microscopic planktonic communities to global fisheries. We report a fundamental dichotomy in the affinity of enzymes for oxygen. The importance of this observation has yet to be fully assessed, but it is predicted to impact the rate at which organic matter is oxidized in hypoxic ecosystems, and the types of organic matter that accumulate. Competition between intracellular enzymes for oxygen may also have impacted microbial strategies of adaptation to suboxia.

microbiology↗

bioRxiv2019

Oxygen supply capacity in animals evolves to meet maximum demand at the current oxygen partial pressure regardless of size or temperature

Physiological oxygen supply capacity is associated with athletic performance and cardiovascular health and is thought to cause hypometabolic scaling in diverse species. Environmental oxygen is widely believed to be limiting of metabolic rate and aerobic scope, setting thermal tolerance and body size limits with implications for species diversity and biogeography. Here we derive a quantifiable linkage between maximum and basal metabolic rate and their temperature, size and oxygen dependencies. We show that, regardless of size or temperature, the capacity for oxygen supply precisely matches the maximum evolved demand at the highest persistently available oxygen pressure which, for most species assessed, is the current atmospheric pressure. Any reduction in oxygen partial pressure from current values will result in a decrement in maximum metabolic performance. However, oxygen supply capacity does not constrain thermal tolerance and does not cause hypometabolic scaling. The critical oxygen pressure, typically viewed as an indicator of hypoxia tolerance, instead reflects adaptations for aerobic scope. This simple new relationship redefines many important physiological concepts and alters their ecological interpretation.\n\nOne sentence summary: Metabolism is not oxygen limited

physiology↗