抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

A review of central 5-HT receptors and their function

Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human β2-adrenergic receptor–T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein–coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the β2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.

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High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor

Although chemotherapy is designed to eradicate tumor cells it also has a significant impact on normal tissues. These host-responses can have large effects on the efficacy of treatment and overall survival. Fatty acids are increasingly recognized to play important signaling roles. 12-S-HHT and 16:4(n-3) are two platinum-induced fatty acids (PIFAs) that induce systemic resistance to a broad range of DNA-damaging chemotherapeutics. PIFAs exert their chemoprotective effect on tumor cells via an indirect mechanism involving splenic F4/80 + /CD11b low macrophages. Here we identified GPR120 on mouse and human splenic macrophages as the relevant receptor for 16:4(n-3). GPR120 (FFAR4) is a free fatty acid receptor that binds medium- to long-chain fatty acids and omega-3 fatty acids and is involved in anti-inflammatory response and metabolic control. Although both GPR40 (FFAR1) and GPR120 can be activated by 16:4(n-3) in vitro, only inhibition or genetic loss of GPR120 was able to block 16:4(n-3)-mediated chemoresistance in vivo. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA 2 activity in splenic macrophages resulting in the production and secretion of resistance-inducing lysophosphatidylcholine 24:1 (LPC(24:1)). Taken together, we identified a novel function for GPR120. Activation by 16:4(n-3) leads to enhanced cPLA 2 activity and production of LPC(24:1) resulting in chemotherapy resistance. Citation Format: Julia Houthuijzen, Ilse Oosterom, Brian Hudson, Akira Hirasawa, Laura Daenen, Chelsea McLean, Steffen Hansen, Marijn van Jaarsveld, Daniel Peeper, sahar Jafari Sadatmand, Jeanine Roodhart, Chris van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest. GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 307.

Abstract 307: GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy

Many wild-type G-protein-coupled receptors display relatively low levels of constitutive activity and thus identification of ligands with inverse agonist activity can be difficult. Two assays are available that monitor receptor interaction with a G protein, GTPase activity assays and [35S]GTPγS binding assays. GTPase assays are, however, frequently limited by high background. The fraction of membrane GTPase activity contributed by the constitutive activity of a receptor can be enhanced by addition of a recombinant regulator of G protein signalling protein to the assay. Detection of inverse agonists is then improved markedly. [35S]GTPγS binding assays for the detection of inverse agonists have historically been limited to receptors that activate pertussis toxin-sensitive G proteins. Introduction of a selective immunoprecipitation step using a G protein subtype specific antiserum allows this approach to be used for all G protein families. Application of these novel approaches, combined with the use of receptor–G protein fusion proteins to optimise receptor to G protein information transfer allows quantitative analysis of the extent of enhancement of constitutive activity produced by mutation of receptor or G protein.

Novel approaches to enhance the detection of receptor constitutive activity and inverse agonists

Agonist-Mediated Turnover of G-Protein α-Subunit Palmitoyl Groups

Receptors which identify neurotransmitters, hormones and growth factors can be subdivided into three broad classes. These are (1) receptors which allow direct gating of ions; (2) receptors which indirectly control the activity of effector systems which are either ion channels or enzymes which generate intracellular second messengers; and (3) receptors which express tyrosyl kinase activity. This review will focus on the mechanism of action of the second class of receptors, because in every case receptor control of effector function is absolutely dependent upon the intermediate activation of one or more members of a family of highly homologous guanine nucleotide-binding proteins (G-proteins). G-proteins which are implicated in cellular signalling processes are found widely throughout evolution. Highly conserved G-proteins have been identified either via cDNA cloning or immunological means in each of mammals, birds, amphibia, invertebrates, yeast and slime moulds. Preliminary evidence has also been presented to indicate the expression of related proteins in both green plants and bacteria. It should be remembered however that not all proteins which bind and hydrolyse GTP are likely to be involved in cellular signalling processes. For example, factors involved in protein synthesis initiation and elongation require GTP, as do the α- and β-subunits of the microtubule-forming protein, tubulin. Further, a series of low-Mr (21-28 kDa), GTP-utilizing polypeptides have been identified, including members of the ras, ral, rho, ARF and smg families of proteins. A number of these proteins have been implicated in signalling processes, particularly in relation to the control of mitogenesis, but further roles, especially in relation to control of secretory processes, appear likely, particularly when genetic information from yeast systems is taken into consideration.

Pertussis Toxin-sensitive GTP-binding Proteins in Neuronal Tissues: Recent Insights into Expression and Function

Antisera which recognise the ∝ subunits of individual members of the family of guanine nucleotide binding proteins (G-proteins) have been produced using either the purified proteins or peptides corresponding to parts of their sequence. These have been used to investigate alterations in expression of these G-proteins during development in a range of systems.

Graeme Milligan

Papers

Abstract 307: GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy

Novel approaches to enhance the detection of receptor constitutive activity and inverse agonists

Agonist-Mediated Turnover of G-Protein α-Subunit Palmitoyl Groups

Pertussis Toxin-sensitive GTP-binding Proteins in Neuronal Tissues: Recent Insights into Expression and Function

The use of specific antisera to study the developmental regulation of guanine nucleotide binding proteins