Clathrin-mediated endocytosis (CME) is vital for the internalization of most cell-surface proteins. In CME, plasma membrane-binding clathrin adaptors recruit and polymerize clathrin to form clathrin-coated pits into which cargo is sorted. Assembly polypeptide 2 (AP2) is the most abundant adaptor and is pivotal to CME. Here, we determined a structure of AP2 that includes the clathrin-binding β2 hinge and developed an AP2-dependent budding assay. Our findings suggest that an autoinhibitory mechanism prevents clathrin recruitment by cytosolic AP2. A large-scale conformational change driven by the plasma membrane phosphoinositide phosphatidylinositol 4,5-bisphosphate and cargo relieves this autoinhibition, triggering clathrin recruitment and hence clathrin-coated bud formation. This molecular switching mechanism can couple AP2's membrane recruitment to its key functions of cargo and clathrin binding.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333214 | PMC |
| http://dx.doi.org/10.1126/science.1254836 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Investigating Complexin-Membrane Interactions Using NMR and Optical Methods.
Methods Mol Biol
January 2025
Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
Complexins are a family of small presynaptic proteins that regulate neurotransmitter release at nerve terminals and are highly conserved in evolution. While direct interactions with SNARE proteins are critical for all complexin functions, binding of their disordered C-terminal domains (CTD) to membranes, especially to synaptic vesicle membranes, is essential for the ability of complexin to inhibit vesicle release. Furthermore, while some complexin CTDs possess an endogenous affinity for membranes, other complexin isoforms are subject to lipidation at their C-termini, which is presumed to confer additional membrane binding.
View Article and Find Full Text PDFMolecular Dynamics Simulations of the SNARE Complex Interacting with Synaptotagmin, Complexin, and Lipid Bilayers.
Methods Mol Biol
January 2025
Departments of Neurology, and Anatomy and Cell Biology, Wayne State University School of Medicine, University Health Center, Detroit, MI, USA.
Molecular dynamics (MD) simulations enable in silico investigation of the dynamic behavior of proteins and protein complexes. Here, we describe MD simulations of the SNARE bundle forming the complex with the neuronal proteins Synaptotagmin-1 (Syt1) and Complexin (Cpx). Syt1 is the synaptic vesicle (SV) protein that serves as the neuronal calcium sensor and triggers synaptic fusion upon calcium binding, and this process is promoted and accelerated by Cpx.
View Article and Find Full Text PDFInhibition of RIPK1-driven necroptosis ameliorates inflammatory hyperalgesia caused by lipopolysaccharide: involvement of TLR-, NLRP3-, and caspase-11-mediated signaling pathways.
Cell Mol Biol (Noisy-le-grand)
January 2025
Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Türkiye.
Article Synopsis
- Recent research indicates that blocking the RIPK1/RIPK3/MLKL necrosome can help reduce inflammatory pain linked to conditions like demyelination in the central nervous system.
- This study tests necrostatin-1s (Nec-1s), a specific RIPK1 inhibitor, on LPS-induced inflammatory pain in male mice, assessing pain sensitivity through hot plate tests and examining related protein changes.
- Results show that Nec-1s not only prevents LPS-induced pain relief but also reverses the activation of key proteins and signals involved in inflammation and demyelination, suggesting that RIPK1 inhibitors could be a promising treatment for managing inflammatory pain.
Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.
Proc Natl Acad Sci U S A
January 2025
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear.
View Article and Find Full Text PDFHsa_circ_0109623 regulates the progression of autoimmune liver disease through Hsa_miR_146b-3p/Sortilin 1-mediated activation of CD4+ T cells.
Hepatol Commun
January 2025
Department of Rheumatology, Inner Mongolia Autonomous Region Hospital of Traditional Chinese Medicine, Hohhot, P.R. China.
Background: Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune-mediated liver inflammation. Despite its global prevalence, the pathogenesis of AIH remains poorly understood, and there is a lack of specific biomarkers and targeted treatments. This study aimed to investigate the role of hsa_circ_0109623, hsa-miR-146b-3p, and Sortilin 1 (SORT1) in AIH and their potential as therapeutic targets.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!