Biology subjects

Yuan, C.-C.

Publications and source records attributed to Yuan, C.-C..

3 recordsLinked to original sources

bioRxiv2023

The mitochondrial calcium uniporter transports Ca2+ via a ligand-relay mechanism.

The mitochondrial calcium uniporter (mtCU) is a multicomponent Ca2+-specific channel that imparts mitochondria with the capacity to sense the cytosolic calcium signals. The metazoan mtCU comprises the pore-forming subunit MCU and the essential regulator EMRE, arranged in a tetrameric channel complex, and the Ca2+ sensing peripheral proteins MICU1-3. The mechanism of mitochondrial Ca2+ uptake by mtCU and its regulation is poorly understood. Our analysis of MCU structure and sequence conservation, combined with molecular dynamics simulations, mutagenesis, and functional studies, led us to conclude that the Ca2+ conductance of MCU is driven by a ligand-relay mechanism, which depends on stochastic structural fluctuations in the conserved DxxE sequence. In the tetrameric structure of MCU, the four glutamate side chains of DxxE (the E-ring) chelate Ca2+ directly in a high-affinity complex (site 1), which blocks the channel. The four glutamates can also switch to a hydrogen bond-mediated interaction with an incoming hydrated Ca2+ transiently sequestered within the D-ring of DxxE (site 2), thus releasing the Ca2+ bound at site 1. This process depends critically on the structural flexibility of DxxE imparted by the adjacent invariant Pro residue. Our results suggest that the activity of the uniporter can be regulated through the modulation of local structural dynamics. A preliminary account of this work was presented at the 67th Annual Meeting of the Biophysical Society in San Diego, CA, February 18-22, 2023

biochemistry↗

bioRxiv2019

EZH2 inhibition results in genome-wide PRC2 redistribution

Histone methyltransferase polycomb repressive complex 2 (PRC2) plays a critical role in cell fate determination, and its catalytic subunit EZH2 is a key oncogenic driver in GCB-DLBCL. EZH2 inhibition in some GCB-DLBCL cell models leads to a global loss of H3K27me3, the derepression of a subset of silenced PRC2 target genes, and ultimately cell death. Here we show that EZH2 inhibition causes global redistribution of PRC2 components. We observe a reduction in the already-low levels of PRC2 at active genes. On the other hand, focal PRC2 accumulation and concomitant H3K27me3 retention occur at many canonical embryonic stem cell PRC2 nucleation sites. PRC2 accumulation is also enriched in plasma/memory cell genes repressed by PRC2 activity in the germinal center. We see PRC2 redistribution to, and H3K27me3 retention at, differentiation-related genes not only in cell lines that are insensitive to killing by EZH2 inhibition, but also in sensitive cell lines. Thus, PRC2 redistribution to B cell differentiation genes is not sufficient to explain the resistance to EZH2 inhibitors in some DLBCL cell lines.

genomics↗

bioRxiv2017

Single Cardiac Ventricular Myosins Change Step-Size with Loading

The cardiac myosin motor powers the beating heart by catalyzed ATPase free energy conversion to contractile work. Transgenic mouse models for heart disease express mouse -cardiac myosin heavy chain with human essential light chain (ELC) in wild type (WT), or hypertrophic cardiomyopathy linked mutant forms, A57G or E143K. Mutants modify the ELC actin binding N-terminus or C-terminus regions. Motility and single myosin mechanical characteristics show stark contrasts between the motors related to their average force, power, and displacement while all indicate the ability to down-shift ensemble step-size with increasing load. A57G and E143K consume more ATP than control WT in the presence of actin with A57G upregulating and E143K downregulating power compared with WT. Higher ATP consumption and downregulated power in E143K implies a lower unitary force. Effects on power are consistent with an A57G that impairs the ELC N-terminus actin binding and an E143K that reduces lever-arm rigidity.

biophysics↗