Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease
- PDF / 2,681,023 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 56 Downloads / 174 Views
Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease Ana‑Nicoleta Bondar1 Received: 14 July 2020 / Accepted: 4 November 2020 © The Author(s) 2020
Abstract Transmembrane substrate cleavage by the small Escherichia coli rhomboid protease GlpG informs on mechanisms by which lipid interactions shape reaction coordinates of membrane-embedded enzymes. Here, I review and discuss new work on the molecular picture of protein–lipid interactions that might govern the formation of the substrate–enzyme complex in fluid lipid membranes. Negatively charged PG-type lipids are of particular interest, because they are a major component of bacterial membranes. Atomistic computer simulations indicate POPG and DOPG lipids bridge remote parts of GlpG and might pre-occupy the substrate-docking site. Inhibition of catalytic activity by PG lipids could arise from ligand-like lipid binding at the active site, which could delay or prevent substrate docking. Dynamic protein–lipid H-bond networks, water access to the active site, and fluctuations in the orientation of GlpG suggest that GlpG has lipid-coupled dynamics that could shape the energy landscape of transmembrane substrate docking. Graphic Abstract
Keywords Lipid–protein coupling · Intramembrane protease · GlpG · Phosphatidylglycerol · Hydrogen bonding
Introduction Rhomboid proteases are membrane-embedded enzymes that cleave substrates to activate signaling paths. These proteases were initially identified in Drosophila (Bier et al. 1989), where Rhomboid-1 cleaves the membrane-anchored * Ana‑Nicoleta Bondar [email protected]‑berlin.de 1
Freie Universität Berlin, Department of Physics, Theoretical Molecular Biophysics, Arnimallee 14, 14195 Berlin, Germany
substrate Spitz, activating the epidermal growth factor (EGF) receptor (Urban et al. 2001). Rhomboid proteases are implicated in, e.g., wound healing (Cheng et al. 2011), cancer (Adrain et al. 2011; Yan et al. 2008; Zou et al. 2009), diabetes (Walder et al. 2005), and malaria infection (Baker et al. 2006). An intriguing feature of rhomboid proteases is that they couple tightly to the membrane: The membrane constrains the folding pathway of the E. coli rhomboid protease, GlpG (Schafer et al. 2016), and the catalytic activity of rhomboids depends drastically on the surrounding lipid environment (Urban and Wolfe 2005). Significant impact of
13
Vol.:(0123456789)
A.-N. Bondar
the lipid membrane composition on substrate-cleaving properties was also observed for two other membrane-embedded proteases, presenilin, whose transmembrane substrates include amyloid precursor protein (Osenkowski et al. 2008), and signal peptide peptidase, which cleaves signal peptides (Narayanan et al. 2007). The rhomboid protease of E. coli, GlpG (Fig. 1), is well characterized by structural biology and biochemistry (for reviews see, e.g., Bondar 2016; Bondar and Lemieux 2019; Brooks and Lemieux 2013; Düsterhöft et al. 2017; Strisovsky 2016; Urban 2010, 2013)) and thus a valuable model system to decipher how lipids shape rea
Data Loading...
