Biology subjects

Huang, Y.-m.

Publications and source records attributed to Huang, Y.-m..

2 recordsLinked to original sources

bioRxiv2025

Unraveling the Molecular Mechanisms of ABHD5 Membrane Targeting

ABHD5 is a master regulator of PNPLA family lipases, particularly PNPLA2 (ATGL), the rate-limiting triglyceride (TAG) hydrolase in metabolic tissues. Despite its central role in lipid metabolism, the molecular basis by which ABHD5 recognizes membranes and regulates enzymatic activity remains poorly understood. Here, we report an integrated computational-experimental study revealing how the /{beta}-hydrolase domain-containing protein 5 (ABHD5) dynamically engages lipid droplet (LD) and endoplasmic reticulum membranes to control lipolytic activation. Using multiscale molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and site-directed mutagenesis, we uncover a sequential dual-site membrane recognition mechanism, where the N-terminus provides initial anchoring and a lid helix within the insertion segment forms a crucial secondary contact. Membrane binding triggers a dramatic conformational switch in this lid, expanding the pseudosubstrate pocket and transforming ABHD5 into an active and membrane-localized regulator. This structural transition is coupled to membrane remodeling, inducing localized curvature and forming a triacylglycerol-enriched nanodomain beneath the ABHD5 pseudosubstrate pocket. This bidirectional interaction between ABHD5 and the membrane provides a persuasive mechanism for interfacial activation. Our findings establish new principles for how LD-binding proteins achieve functional specificity through membrane-dependent regulation, offering novel molecular targets for interventions in metabolic diseases. TeaserA key protein controls fat breakdown by changing shape when it binds membranes and reshapes local fat droplets.

biophysics↗

bioRxiv2024

In silico discovery of potential inhibitors targeting the MEIG1-PACRG complex for male contraceptive development

The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) is a critical determinant of spermiogenesis, the process by which round spermatids mature into functional spermatozoa. Disruption of the MEIG1-PACRG complex can impair sperm development, highlighting its potential as a therapeutic target for addressing male infertility or for the development of non-hormonal contraceptive methods. This study used virtual screening, molecular docking, and molecular dynamics (MD) simulations to identify small molecule inhibitors targeting the MEIG1-PACRG interface. MD simulations provided representative protein conformations, which were used to virtually screen a library of over 800,000 compounds, resulting in 48 high-ranking candidates for each protein. PACRG emerged as a favorable target due to its flexible binding pockets and better docking scores compared to MEIG1. Key binding residues with compounds included W50, Y68, N70, and E74 on MEIG1, and K93, W96, E101, and H137 on PACRG. MD simulations revealed that compound stability in MEIG1 complexes is primarily maintained by hydrogen bonding with E74 and {pi}-{pi} stacking interactions with W50 and Y68. In PACRG complexes, compound stabilization is facilitated by hydrogen bonding with E101 and {pi}-{pi} interactions involving W96 and H137. These findings highlight distinct molecular determinants of ligand binding for each protein. Our work provides mechanistic insights and identifies promising compounds for further experimental validation, establishing a foundation for developing MEIG1-PACRG interaction inhibitors as male contraceptives.

pharmacology and toxicology↗