NMR solution structure of C2 domain of MFG-E8 and insights into its molecular recognition with phosphatidylserine

Ye, Hong; Li, Baihong; Vivekanandan, Subramanian; Choi, Bo-Hwa; Yu, Lian; Harikishore, Amaravadhi; Chakraborty, Goutam; Baek, Kwanghee; Yoon, Ho Sup

doi:10.1016/j.bbamem.2012.12.009

Cited by 30 publications

(44 citation statements)

References 28 publications

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“…The spikes 1 and 3 protrude from the beta-barrel core and display water-exposed hydrophobic residues, which were shown to be critical for the phospholipid binding based on mutagenesis studies. Moreover, 3D structure of mouse MFG-E8 F5/8-C2 domain in solution has recently been determined by nuclear magnetic resonance (NMR) spectroscopy [ 40 ] ( Fig. 1.5b ), indicating similarity of the previously determined crystal structure of bovine MFG-E8 C2-domain to the structure of mouse MFG-E8 C2-domain in solution.…”

Section: The F5/8-type C Domainsmentioning

confidence: 94%

“…1.5b ), indicating similarity of the previously determined crystal structure of bovine MFG-E8 C2-domain to the structure of mouse MFG-E8 C2-domain in solution. The binding between the F5/8-C2 domain and phosphatidylserine was characterized by 31 P-NMR, verifying that positively charged and aromatic amino acid residues clustered in the spikes 1 and 3 plays key roles in the binding, and presumably in the recognition of apoptotic cells exposing phosphatidylserine [ 40 ]. Using the MOE program, 3D structure of human MFG-E8 F5/8-C1 and -C2 domains can also be predicted, and is shown together with the predicted EGF-like domain in Fig.…”

Section: The F5/8-type C Domainsmentioning

confidence: 99%

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MFG-E8: Origin, Structure, Expression, Functions and Regulation

Oshima

Yasueda

Nishio

et al. 2014

MFG-E8 and Inflammation

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Milk Fat Globule-Epidermal Growth Factor-Factor 8 (MFG-E8) with bivalent binding activity to integrin receptors and acidic phospholipids is a secretary glycoprotein exhibiting versatile functions in cell physiology affecting health and diseases. Recent progress in genomics and structural biology studies, in addition to long time accumulation of classical biochemical studies, has been showing its unique molecular structure advantageous to the link between cells and their target cells as well as molecular complexes and its critical roles in regulating infl ammation and immunity. MFG-E8 is expressed and secreted by a variety of cells and tissues, especially professional and non-professional phagocytes such as macrophages, immature dendritic cells and the epithelial cells of mammary glands and epididymis. Although MFG-E8 expression has been shown to be up-regulated by a lactogenic hormone, prolactin (PRL), and neuronal chemokine, fractalkine, molecular mechanisms involved in MFG-E8 expression in health and disease states remain largely unknown. The secreted MFG-E8 specifi cally recognizes the acidic phospholipids and opsonized the targets to be cleared by phagocytosis mainly in paracrine and occasionally in endocrine manners. In addition to the enhancing role in phagocytosis, MFG-E8 binds to its target cells expressing MFG-E8 receptors and acts as a ligand, which modulates infl ammatory responses. Moreover, MFG-E8 alone shows ligand activity to intestinal epithelial cells locally exposing the acidic phospholipids and vascular endothelial cells expressing the integrins.

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Section: The F5/8-type C Domainsmentioning

confidence: 94%

Section: The F5/8-type C Domainsmentioning

confidence: 99%

MFG-E8: Origin, Structure, Expression, Functions and Regulation

Oshima

Yasueda

Nishio

et al. 2014

MFG-E8 and Inflammation

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“…It forms a pore-like oligomeric structure that induces cation selective single channel currents across negatively charged planar lipid bilayers that contain either PS or phosphatidylinositol [160]. Lactadherin, which inhibits the translocation of nascent polypeptide chains across the endoplasmic reticulum, binds tightly to PS through its C 2 domain [161,162]. …”

Section: Phosphatidylserine In Neuronal Signal Transductionmentioning

confidence: 99%

Phosphatidylserine in the brain: Metabolism and function

Kim

Huang

Spector

2014

Progress in Lipid Research

277

180

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Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine in reactions are catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.

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“…After treatment, footprint-like pattern of MFG-E8-L in the ECM effectively disappeared although collagen IV was unaffected (Fig. These spikes have been suggested as the essential motifs for direct binging with PS (Shao et al 2008;Ye et al 2013). Detergent-sensitive MFG-E8 localization in the cell substratum was also observed when cells were cultured in the EV-free medium (Fig.…”

Section: L10mentioning

confidence: 78%

“…The C-terminus C2 domain of MFG-E8 has high binding activity toward anionic phospholipids, especially phosphatidylserine (PS) (Oshima et al 2002;Shao et al 2008;Ye et al 2013). MFG-E8 thus specifically binds lipid bilayer exposing PS such as the cell membrane of apoptotic cells and extracellular vesicles (EVs) (Hanayama et al 2002;Oshima et al 2002;Th ery et al 2009;Raposo & Stoorvogel 2013).…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle‐mediated MFG‐E8 localization in the extracellular matrix is required for its integrin‐dependent function in mouse mammary epithelial cells

et al. 2017

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Milk fat globule-EGF factor 8 (MFG-E8) is a divalent-binding secretory protein possessing an Arg-Gly-Asp (RGD) motif and a phosphatidylserine (PS)-binding motif. This protein has been shown to be involved in mammary gland development and morphogenesis. Integrin-binding activity is necessary for these MFG-E8-dependent cell processes. Although the target cells and molecules of MFG-E8 in the cellular microenvironment are important to understand its physiological function, its localization is largely unclear. Here, we found that mouse MFG-E8 localized to the basal lamina of the mammary gland during involution. In a model system of mammary COMMA-1D cells, exogenously and endogenously expressed MFG-E8 was deposited in the extracellular matrix (ECM) with membranous particles dependently on the PS-binding motifs in the discoidin domains that were essential for association ability to extracellular vesicles (EVs). These data showed the basal MFG-E8 localization mechanism in which EVs served as a scaffold. Such an immobilized MFG-E8 associating with cell substrata but not soluble one in the culture media promoted integrin-dependent suppression of β-casein expression. These results suggest that MFG-E8 requires EVs to transduce cellular signals from the basolateral side of the adhesion cells by accumulating in ECM.

show abstract

NMR solution structure of C2 domain of MFG-E8 and insights into its molecular recognition with phosphatidylserine

Cited by 30 publications

References 28 publications

MFG-E8: Origin, Structure, Expression, Functions and Regulation

MFG-E8: Origin, Structure, Expression, Functions and Regulation

Phosphatidylserine in the brain: Metabolism and function

Extracellular vesicle‐mediated MFG‐E8 localization in the extracellular matrix is required for its integrin‐dependent function in mouse mammary epithelial cells

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