RESUMEN
Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness.
Asunto(s)
Retículo Endoplásmico/metabolismo , Ácidos Grasos/metabolismo , Membranas Intracelulares/metabolismo , Fluidez de la Membrana , Proteínas de la Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Regulación Fúngica de la Expresión Génica , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Simulación de Dinámica Molecular , Mutación , Conformación Proteica en Hélice alfa , Estabilidad Proteica , Proteolisis , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Transducción de Señal , Estearoil-CoA Desaturasa , Relación Estructura-Actividad , Factores de Transcripción/química , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
Biological membranes are dynamic and complex assemblies of lipids and proteins. Eukaryotic lipidomes encompass hundreds of distinct lipid species and we have only begun to understand their role and function. This review focuses on recent advances in the field of lipid sensors and discusses methodical approaches to identify and characterize putative sensor domains. We elaborate on the role of integral and conditionally membrane-associated sensor proteins, their molecular mechanisms, and identify open questions in the emerging field of membrane homeostasis.
Asunto(s)
Membrana Celular/química , Membrana Celular/metabolismo , Homeostasis , Lípidos de la Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Humanos , Lípidos de la Membrana/química , Proteínas de la Membrana/químicaRESUMEN
Biological membranes are a defining feature of cellular life. They serve as selective diffusion barriers, compartmentalize biochemical processes and protect the cellular milieu. We are only beginning to understand the principles underlying their homeostasis and the functional relevance of their complex compositions. Here, we summarize some recent evidences that suggest an intense crosstalk between the pathways of protein quality control and lipid homeostasis. We discuss paradigms of lipid regulation by protein degradation machineries and highlight the intricate connections between lipid droplet morphology, membrane biogenesis and ER-stress.
