Biology subjects

Braun, R. J.

Publications and source records attributed to Braun, R. J..

3 recordsLinked to original sources

bioRxiv2023

Bsc2 is a novel regulator of triglyceride lipolysis that demarcates a lipid droplet subpopulation

Cells store lipids in the form of triglyceride (TG) and sterol-ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs, and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal Tld1s HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis, but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, over-expression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations.

cell biology↗

bioRxiv2022

Capturing the liquid-crystalline phase transformation: Implications for protein targeting to sterol ester-rich lipid droplets

Lipid droplets are essential organelles that store and traffic neutral lipids. The phospholipid monolayer surrounding their neutral lipid core engages with a highly dynamic proteome that changes according to cellular and metabolic conditions. Recent work has demonstrated that when the abundance of sterol esters increases above a critical concentration, such as under conditions of starvation or high LDL exposure, the lipid droplet core can undergo an amorphous to liquid-crystalline phase transformation. Herein we study the consequences of this transformation on the physical properties of lipid droplets that are thought to regulate protein association. Using simulations of different sterol-ester concentrations we have captured the liquid-crystalline phase transformation at the molecular level, highlighting the alignment of sterol esters in alternating orientations to form concentric layers. We demonstrate how ordering in the core permeates into the neutral lipid/phospholipid interface, changing the magnitude and nature of neutral lipid intercalation and inducing ordering in the phospholipid monolayer. Increased phospholipid packing is concomitate with altered surface properties, including smaller area per phospholipid and substantially reduced packing defects. Additionally, the ordering of sterol esters in the core causes less hydration in more ordered regions. We discuss these findings in the context of their expected consequences for preferential protein recruitment to lipid droplets under different metabolic conditions.

biophysics↗

bioRxiv2021

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)

biochemistry↗