The PX-BAR membrane-remodeling unit of sorting nexin 9

Department of Physical Biochemistry, Max-Planck-Institute for Molecular Physiology, Dortmund, Germany.
The EMBO Journal (Impact Factor: 10.43). 12/2007; 26(22):4788-800. DOI: 10.1038/sj.emboj.7601889
Source: PubMed


Sorting nexins (SNXs) form a family of proteins known to interact with components in the endosomal system and to regulate various steps of vesicle transport. Sorting nexin 9 (SNX9) is involved in the late stages of clathrin-mediated endocytosis in non-neuronal cells, where together with the GTPase dynamin, it participates in the formation and scission of the vesicle neck. We report here crystal structures of the functional membrane-remodeling unit of SNX9 and show that it efficiently tubulates lipid membranes in vivo and in vitro. Elucidation of the protein superdomain structure, together with mutational analysis and biochemical and cell biological experiments, demonstrated how the SNX9 PX and BAR domains work in concert in targeting and tubulation of phosphoinositide-containing membranes. The study provides insights into the SNX9-induced membrane modulation mechanism.

Download full-text


Available from: Alexey Rak, Aug 21, 2014
16 Reads
  • Source
    • "Crystal structures of numerous BAR domains have been solved, but only few studies have provided insight into the structural organization of individual domains relative to one another in full-length BAR domain proteins. For sorting nexin 9 (Snx9), endophilin, APPL1, and syndapin-1, their respective accessory domains were all associated with either the side or the tip of the BAR domain (Li et al., 2007; Pylypenko et al., 2007; Rao et al., 2010; Wang et al., 2008; Zhu et al., 2007). To investigate the structural interdomain arrangement in PICK1, which is believed to underlie the auto-inhibition mechanism, we engaged in small-angle X-ray scattering (SAXS) studies of full-length PICK1 in solution. "
    [Show abstract] [Hide abstract]
    ABSTRACT: PICK1 is a neuronal scaffolding protein containing a PDZ domain and an auto-inhibited BAR domain. BAR domains are membrane-sculpting protein modules generating membrane curvature and promoting membrane fission. Previous data suggest that BAR domains are organized in lattice-like arrangements when stabilizing membranes but little is known about structural organization of BAR domains in solution. Through a small-angle X-ray scattering (SAXS) analysis, we determine the structure of dimeric and tetrameric complexes of PICK1 in solution. SAXS and biochemical data reveal a strong propensity of PICK1 to form higher-order structures, and SAXS analysis suggests an offset, parallel mode of BAR-BAR oligomerization. Furthermore, unlike accessory domains in other BAR domain proteins, the positioning of the PDZ domains is flexible, enabling PICK1 to perform long-range, dynamic scaffolding of membrane-associated proteins. Together with functional data, these structural findings are compatible with a model in which oligomerization governs auto-inhibition of BAR domain function. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Structure 06/2015; 23(7). DOI:10.1016/j.str.2015.04.020 · 5.62 Impact Factor
  • Source
    • "As CCPs mature, BAR domain proteins of increasing curvature are recruited. These include FBP17, with a curvature preference for a membrane sphere of 70 nm in diameter (Shimada et al., 2007), substantially larger than FCHo and SNX9, which can adopt two different conformations that yield different membrane curvatures (Pylypenko et al., 2007), possibly facilitating constriction (Posor et al., 2013). Finally, amphiphysin and endophilin, N-BAR proteins with a preference for highly bent membranes of about 25–30 nm in diameter, are recruited (Gallop et al., 2006; Peter et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Biological membranes undergo constant remodeling by membrane fission and fusion to change their shape and to exchange material between subcellular compartments. During clathrin-mediated endocytosis, the dynamic assembly and disassembly of protein scaffolds comprising members of the bin-amphiphysin-rvs (BAR) domain protein superfamily constrain the membrane into distinct shapes as the pathway progresses toward fission by the GTPase dynamin. In this Review, we discuss how BAR domain protein assembly and disassembly are controlled in space and time and which structural and biochemical features allow the tight regulation of their shape and function to enable dynamin-mediated membrane fission.
    Cell 02/2014; 156(5):882-892. DOI:10.1016/j.cell.2014.02.017 · 32.24 Impact Factor
  • Source
    • "SNX1 and SNX2 function in endosome trafficking. Although SNX1 and SNX2 lack the SH3 domain for N-WASP binding, another Arp2/3 complex activating protein, WASH, reportedly associates with SNX1 and SNX2 [35,36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eukaryotic cells have complicated membrane systems. The outermost plasma membrane contains various substructures, such as invaginations and protrusions, which are involved in endocytosis and cell migration. Moreover, the intracellular membrane compartments, such as autophagosomes and endosomes, are essential for cellular viability. The Bin-Amphiphysin-Rvs167 (BAR) domain superfamily proteins are important players in membrane remodeling through their structurally determined membrane binding surfaces. A variety of BAR domain superfamily proteins exist, and each family member appears to be involved in the formation of certain subcellular structures or intracellular membrane compartments. Most of the BAR domain superfamily proteins contain SH3 domains, which bind to the membrane scission molecule, dynamin, as well as the actin regulatory WASP/WAVE proteins and several signal transduction molecules, providing possible links between the membrane and the cytoskeleton or other machineries. In this review, we summarize the current information about each BAR superfamily protein with an SH3 domain(s). The involvement of BAR domain superfamily proteins in various diseases is also discussed.
    12/2012; 2(1):91-117. DOI:10.3390/membranes2010091
Show more