Structural basis of Dscam isoform specificity

The Dscam gene gives rise to thousands of diverse cell surface receptors thought to provide homophilic and heterophilic recognition specificity for neuronal wiring and immune responses. Mutually exclusive splicing allows for the generation of sequence variability in three immunoglobulin ecto-domains, D2, D3 and D7. We report X-ray structures of the amino-terminal four immunoglobulin domains (D1-D4) of two distinct Dscam isoforms. The structures reveal a horseshoe configuration, with variable residues of D2 and D3 constituting two independent surface epitopes on either side of the receptor. Both isoforms engage in homo-dimerization coupling variable domain D2 with D2, and D3 with D3. These interactions involve symmetric, antiparallel pairing of identical peptide segments from epitope I that are unique to each isoform. Structure-guided mutagenesis and swapping of peptide segments confirm that epitope I, but not epitope II, confers homophilic binding specificity of full-length Dscam receptors. Phylogenetic analysis shows strong selection of matching peptide sequences only for epitope I. We propose that peptide complementarity of variable residues in epitope I of Dscam is essential for homophilic binding specificity.     

Structural basis for glycosphingolipid transfer specificity

Lipid transfer proteins are important in membrane vesicle biogenesis and trafficking, signal transduction and immunological presentation processes. The conserved and ubiquitous mammalian glycolipid transfer proteins (GLTPs) serve as potential regulators of cell processes mediated by glycosphingolipids, ranging from differentiation and proliferation to invasive adhesion, neurodegeneration and apoptosis. Here we report crystal structures of apo-GLTP (1.65 A resolution) and lactosylceramide-bound (1.95 A) GLTP, in which the bound glycosphingolipid is sandwiched, after adaptive recognition, within a previously unknown two-layer all-alpha-helical topology. Glycosphingolipid binding specificity is achieved through recognition and anchoring of the sugar-amide headgroup to the GLTP recognition centre by hydrogen bond networks and hydrophobic contacts, and encapsulation of both lipid chains, in a precisely oriented manner within a 'moulded-to-fit' hydrophobic tunnel. A cleft-like conformational gating mechanism, involving two interhelical loops and one alpha-helix of GLTP, could enable the glycolipid chains to enter and leave the tunnel in the membrane-associated state. Mutation and functional analyses of residues in the glycolipid recognition centre and within the hydrophobic tunnel support a framework for understanding how GLTPs acquire and release glycosphingolipids during lipid intermembrane transfer and presentation processes.     

Molecular basis of mechanosensory transduction

Mechanotransduction - a cell's conversion of a mechanical stimulus into an electrical signal - reveals vital features of an organism's environment. From hair cells and skin mechanoreceptors in vertebrates, to bristle receptors in flies and touch receptors in worms, mechanically sensitive cells are essential in the life of an organism. The scarcity of these cells and the uniqueness of their transduction mechanisms have conspired to slow molecular characterization of the ensembles that carry out mechanotransduction. But recent progress in both invertebrates and vertebrates is beginning to reveal the identities of proteins essential for transduction.     

Molecular biological research on Foraminifera

ForaminiferabelongstoSarcodina(Protozoa)andexhibitscytoplasmicorganizationandpseudopdial streamingcharacteristicbroadlyofamoeboidorgan ism[1].Itmainlylivesinthemarineenvironment withamembranous,agglutinatedorcalcareousshell.Asoneofthemostimportantgroupsinmicropaleon tology,Foraminiferahasbeenwidelyusedforthe stratigraphicsubdivision,correlationinpetroleum wellsandforthereconstructionofpaleo environments duringthelastseveraldecades[2,3].Furthermore,sincethe1960swiththestartofDeepSeaDrilling …     

Structural basis for modulation and agonist specificity of HCN pacemaker channels

The family of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are crucial for a range of electrical signalling, including cardiac and neuronal pacemaker activity, setting resting membrane electrical properties and dendritic integration. These nonselective cation channels, underlying the I(f), I(h) and I(q) currents of heart and nerve cells, are activated by membrane hyperpolarization and modulated by the binding of cyclic nucleotides such as cAMP and cGMP. The cAMP-mediated enhancement of channel activity is largely responsible for the increase in heart rate caused by beta-adrenergic agonists. Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore. X-ray crystallographic structures of this C-terminal fragment bound to cAMP or cGMP, together with equilibrium sedimentation analysis, identify a tetramerization domain and the mechanism for cyclic nucleotide specificity, and suggest a model for ligand-dependent channel modulation. On the basis of amino acid sequence similarity to HCN channels, the cyclic nucleotide-gated, and eag- and KAT1-related families of channels are probably related to HCN channels in structure and mechanism.     

Hydrogen bonding and biological specificity analysed by protein engineering

The role of complementary hydrogen bonding as a determinant of biological specificity has been examined by protein engineering of the tyrosyl-tRNA synthetase. Deletion of a side chain between enzyme and substrate to leave an unpaired, uncharged hydrogen-bond donor or acceptor weakens binding energy by only 0.5-1.5 kcal mol-1. But the presence of an unpaired and charged donor or acceptor weakens binding by a further approximately 3 kcal mol-1.     

流感病毒致病的分子基础

自然感染，流感病毒感染的宿主范围有较强的特异性，各毒株所表现的毒力也所不同，决定流感病毒宿主特异性和毒力的因素很多，本文主要从流感病毒的分子水平上来揭示流感病毒的宿主特异性及其毒力差异。     

Molecular basis of photoprotection and control of photosynthetic light-harvesting

In order to maximize their use of light energy in photosynthesis, plants have molecules that act as light-harvesting antennae, which collect light quanta and deliver them to the reaction centres, where energy conversion into a chemical form takes place. The functioning of the antenna responds to the extreme changes in the intensity of sunlight encountered in nature. In shade, light is efficiently harvested in photosynthesis. However, in full sunlight, much of the energy absorbed is not needed and there are vitally important switches to specific antenna states, which safely dissipate the excess energy as heat. This is essential for plant survival, because it provides protection against the potential photo-damage of the photosynthetic membrane. But whereas the features that establish high photosynthetic efficiency have been highlighted, almost nothing is known about the molecular nature of the dissipative states. Recently, the atomic structure of the major plant light-harvesting antenna protein, LHCII, has been determined by X-ray crystallography. Here we demonstrate that this is the structure of a dissipative state of LHCII. We present a spectroscopic analysis of this crystal form, and identify the specific changes in configuration of its pigment population that give LHCII the intrinsic capability to regulate energy flow. This provides a molecular basis for understanding the control of photosynthetic light-harvesting.     

人类合作行为的神经生物基础及脑模型

已有的脑成像研究表明,个体在社会博弈中的合作决策主要激活与认知控制、社会认知以及奖励加工有关的三类大脑神经网络.首先对上述三类大脑系统的功能及其相应的大脑结构和神经回路进行阐述,并对相关的脑成像研究进行回顾.对激素水平的研究发现,催产素能通过增加人们之间的信任来促进合作.在此基础上,介绍新近提出的关于合作的脑机制模型,最后指出这一领域已有研究存在的一些问题以及未来的研究方向.     

Molecular genetic basis of the histo-blood group ABO system

The histo-blood group ABO, the major human alloantigen system, involves three carbohydrate antigens (ABH). A, B and AB individuals express glycosyltransferase activities converting the H antigen into A or B antigens, whereas O(H) individuals lack such activity. Here we present a molecular basis for the ABO genotypes. The A and B genes differ in a few single-base substitutions, changing four amino-acid residues that may cause differences in A and B transferase specificity. A critical single-base deletion was found in the O gene, which results in an entirely different, inactive protein incapable of modifying the H antigen.     

抗纤维结合素单克隆抗体与自身抗原组蛋白免疫交叉反应的分子基础研究

应用免疫扩散和ＷｅｓｔｅｒｎＢｌｏｔ分析证实了抗纤维结合素（Ｆｉｂｒｏｎｅｃｔｉｎ，ＦＮ）单克隆抗体与自身抗原组蛋白（Ｈｉｓｔｏｎｅｓ）发生免疫学交叉反应。通过计算机技术进一步分析了交叉反应的分子基础。在组蛋白和ＦＮ之间有５个氨基酸序列同源性区域被发现。同源性区域与Ｐｏｌｌａｒｄ所预测的组蛋白抗原决定簇相一致（Ｐｏｌｌａｒｄ，１９９０，Ａｕｔｏｉｍｍｕｎｉｔｙ）。根据抗原抗体反应的物理学，化学和免疫学特性，讨论了单克隆抗体与不相关抗原发生交叉反应的可能原因。包括：１．分子模拟－－－氨基酸序列同源性；２．不相关抗原共享的构型表位；３．抗原抗体反应时空间电荷分布；４．反应介质的诱导。组蛋白与某些单克隆抗体发生的交叉反应性揭示了在自身免疫性疾病中抗组蛋白自身抗体产生的可能致病原因。