Abstract
Eukaryotic cell membrane dynamics change in curvature during physiological and pathological processes. In the past ten years, a novel protein family, Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain proteins, has been identified to be the most important coordinators in membrane curvature regulation. The F-BAR domain family is a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily that is associated with dynamic changes in cell membrane. However, the molecular basis in membrane structure regulation and the biological functions of F-BAR protein are unclear. The pathophysiological role of F-BAR protein is unknown. This review summarizes the current understanding of structure and function in the BAR domain superfamily, classifies F-BAR family proteins into nine subfamilies based on domain structure, and characterizes F-BAR protein structure, domain interaction, and functional relevance. In general, F-BAR protein binds to cell membrane via F-BAR domain association with membrane phospholipids and initiates membrane curvature and scission via Src homology-3 (SH3) domain interaction with its partner proteins. This process causes membrane dynamic changes and leads to seven important cellular biological functions, which include endocytosis, phagocytosis, filopodium, lamellipodium, cytokinesis, adhesion, and podosome formation, via distinct signaling pathways determined by specific domain-binding partners. These cellular functions play important roles in many physiological and pathophysiological processes. We further summarize F-BAR protein expression and mutation changes observed in various diseases and developmental disorders. Considering the structure feature and functional implication of F-BAR proteins, we anticipate that F-BAR proteins modulate physiological and pathophysiological processes via transferring extracellular materials, regulating cell trafficking and mobility, presenting antigens, mediating extracellular matrix degradation, and transmitting signaling for cell proliferation.
Highlights
Cell membrane curvature is a micro morphological change involved in many important cellular processes including endocytosis, phagocytosis, exocytosis, angiogenisis, and migration
Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain family is a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily which includes the N-terminal amphipathic helix BAR (N-BAR) domain family and inverse BAR (I-BAR) domain family
We analyzed the structure of F-BAR proteins and proposed a modified characterization model for mammalian F-BAR family, which includes CDC42-interacting protein 4 (CIP4), FES/CIP4 homology (FCH) only (FCHO), Slit-Robo GTPase-activating protein (srGAP), PACSIN, proline-serine-threonine phosphatase-interacting protein (PSTPIP), FCH and double Src homology-3 (SH3) domain proteins (FCHSD), FES/FES related (FER), nitric oxide synthase traffic inducer (NOSTRIN), and growth arrest-specific 7 (GAS7) subfamilies
Summary
Cell membrane curvature is a micro morphological change involved in many important cellular processes including endocytosis, phagocytosis, exocytosis, angiogenisis, and migration. F-BAR proteins are membrane-associated proteins and regulate membrane curvature via binding to cell membrane phospholipids. F-BAR proteins and membrane dynamics As described above, F-BAR protein binds to phospholipids through the N-terminal F-BAR domain and bridges the membrane with cytoskeleton. We analyzed the structure of F-BAR proteins and proposed a modified characterization model for mammalian F-BAR family, which includes CIP4, FCHO, srGAP, PACSIN, PSTPIP, FCHSD, FES/FER, NOSTRIN, and GAS7 subfamilies. F-BAR proteins bind to cell membrane via F-BAR domain association with membrane phospholipids (Figure 2). The opened WASP/N-WASP protein exposes its C-terminal verprolin, cofilin, acidic (VCA) and CDC42Rac interactive binding (CRIB) domains, which is activated and binds to actin-related protein 2/3 (Arp2/3) and G-actin, leading to the nucleation of filamentous actin (F-actin) and polymerization of actin (Figure 2) [10]. Structure and cellular functions of F-BAR family We further analyzed the domain structures, interactions, and specific binding partners of nine F-BAR protein subfamilies (Figure 3A), summarized the cellular functions carried out by different F-BAR protein domain-binding partner interactions (Figure 3B), described the procedure of F-BAR protein-mediated cellular function (Figure 4), and discussed the details below
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