Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

Abstract

A plethora of cell biological processes involve modulations of cellular membranes. By using extended lipid-binding interfaces, some proteins have the power to shape membranes by attaching to them. Among such membrane shapers, the superfamily of Bin–Amphiphysin–Rvs (BAR) domain proteins has recently taken center stage. Extensive structural work on BAR domains has revealed a common curved fold that can serve as an extended membrane-binding interface to modulate membrane topologies and has allowed the grouping of the BAR domain superfamily into subfamilies with structurally slightly distinct BAR domain subtypes (N-BAR, BAR, F-BAR and I-BAR). Most BAR superfamily members are expressed in the mammalian nervous system. Neurons are elaborately shaped and highly compartmentalized cells. Therefore, analyses of synapse formation and of postsynaptic reorganization processes (synaptic plasticity) – a basis for learning and memory formation – has unveiled important physiological functions of BAR domain superfamily members. These recent advances, furthermore, have revealed that the functions of BAR domain proteins include different aspects. These functions are influenced by the often complex domain organization of BAR domain proteins. In this Commentary, we review these recent insights and propose to classify BAR domain protein functions into (1) membrane shaping, (2) physical integration, (3) action through signaling components, and (4) suppression of other BAR domain functions.

Structural History of Human SRGAP2 Proteins

“…In this way, BAR, N-BAR, and certain F-BAR domains that have a concave N-surface associate with cellular membrane invaginations, while I-BARs that have convex N-surfaces associate with membrane protrusions. Consistent with their functions in endocytic processes, the crystal structures of membrane invagination-associating F-BAR family members, for example, FBP17, Syndapin, and FCHo2 (PDB codes 2EFL, 3HAH, and 2V0O, respectively), display a concave N-surface (Kessels and Qualmann 2015). It is therefore surprising to see that the endogenous SRGAP2A is localized to and active in cellular protrusions, such as dendritic spine heads and lamellipodia, and scaffold membrane protrusions, when overexpressed in COS-7 cells [(Guerrier et al 2009; Charrier et al 2012; Fritz et al 2015) and this work].…”

Regulation of neuromuscular junction organization by Rab2 and its effector ICA69 in Drosophila

“…During neuromorphogenesis, these events involve dynamic changes in the neuronal membrane as well as structural changes in the underlying neuronal cytoskeleton (Gallo, 2013;Nelson et al, 2013). Several biochemical and genetic studies have illustrated the role of membrane binding/bending and signaling proteins in neuromorphogenesis, both during neuronal differentiation and in mediating synaptic plasticity (Aspenström, 2014;Govek et al, 2004;Guerrier et al, 2009;Kessels and Qualmann, 2015;Murakoshi et al, 2011;Nahm et al, 2010).…”

“…Bin-Amphiphysin-Rvs (BAR) domain-containing proteins with their membrane-deforming properties have recently emerged as key players in establishing neuronal morphology (Frost et al, 2008Itoh et al, 2005;Kessels and Qualmann, 2015;Rao et al, 2010;Ukken et al, 2016). Studies in Drosophila have also implicated a role of BAR-domain proteins in regulating neuromuscular junction (NMJ) morphology (Chang et al, 2013;Coyle et al, 2004;Rikhy et al, 2002).…”

“…Studies in Drosophila have also implicated a role of BAR-domain proteins in regulating neuromuscular junction (NMJ) morphology (Chang et al, 2013;Coyle et al, 2004;Rikhy et al, 2002). Structural and bioinformatics analyses of several BAR-domain proteins have revealed that, in addition to a BAR module, many of these proteins have motifs that can regulate cytoskeleton and neuronal signaling (Aspenström, 2014;Coyle et al, 2004;Habermann, 2004;Kessels and Qualmann, 2015;Liu et al, 2015). Functional analysis of various BAR-domain proteins in cultured neuronal cells and genetic models are consistent with their role in modulating different aspects of cytoskeletal dynamics and neuronal signaling (Coyle et al, 2004;Dharmalingam et al, 2009;Rodal et al, 2008;StanishnevaKonovalova et al, 2016).…”

“…Moreover, proteins such as Syndapin and Nervous wreck (Nwk) can integrate membrane curvature generation with actin cytoskeletal dynamics in both neuronal and non-neuronal cells (Coyle et al, 2004;Dharmalingam et al, 2009;Kessels and Qualmann, 2006;Qualmann and Kelly, 2000). Similarly, some of the mammalian BAR-domain proteins, for instance RICH1 (also known as ARHGAP17) and oligophrenin 1, contain signaling modules that can directly interact with a variety of small GTPases (Houy et al, 2015;Kessels and Qualmann, 2015;Nadif Kasri et al, 2009;Nahm et al, 2010). Although existing structural, cell biological and biochemical analyses of the BAR-domain protein family elegantly bring out its crucial role in mediating various cellular functions, the in vivo context(s) in which these proteins function and mediate neuronal differentiation remains incompletely understood.…”