Solute carrier spinster homolog 2 (SPNS2), one of only four known major facilitator superfamily (MFS) lysolipid transporters in humans, exports sphingosine-1-phosphate (S1P) across cell membranes. Here, we explore the synergistic effects of lipid binding and conformational dynamics on SPNS2's transport mechanism. Using mass spectrometry, we discovered that SPNS2 interacts preferentially with PI(4,5)P. Together with functional studies and molecular dynamics (MD) simulations, we identified potential PI(4,5)P binding sites. Mutagenesis of proposed lipid binding sites and inhibition of PI(4,5)P synthesis reduce S1P transport, whereas the absence of the N terminus renders the transporter essentially inactive. Probing the conformational dynamics of SPNS2, we show how synergistic binding of PI(4,5)P and S1P facilitates transport, increases dynamics of the extracellular gate, and stabilizes the intracellular gate. Given that SPNS2 transports a key signaling lipid, our results have implications for therapeutic targeting and also illustrate a regulatory mechanism for MFS transporters.
The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to cytosol. Besides, SLC15A4 also functions as a scaffold protein for the recruitment of the adapter TASL for interferon regulatory factor 5 (IRF5) activation downstream of innate immune TLR7-9 signaling. However, the molecular basis for the substrate recognition and TASL recruitment by these membrane proteins is not well understood.
Introduction: Conventional pesticide formulations have been widely used to boost agricultural productivity, but their weak foliar adhesion and instability under UV light during spraying lead to low utilization rates and potential environmental and health hazards. To counter these challenges, the development of nanoformulations represents a pivotal strategy. These advanced formulations are designed to enhance the efficacy of active ingredients (AIs) and reduce ecological impacts, thereby addressing the need for sustainable agricultural development.
Endometriosis and adenomyosis are debilitating gynecological conditions that severely affect the quality of life of women. Traditional diagnostic and treatment methods, including laparoscopic surgery and hormonal therapy, face significant limitations such as incomplete lesion detection, high recurrence rates, and adverse side effects. Emerging bioengineering technologies offer promising solutions for precise diagnosis and therapy of these diseases.
Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.
Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.
Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA (Li W).
