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Nature论文导读 0817

时间: 2017年08月30日 | 作者: admin | 来源: 未知
1 【古生物】 New gliding mammaliaforms from the Jurassic 侏罗纪新型滑翔哺乳形类动物化石 Zhe-Xi Luo (罗哲西,芝加哥大学) et al. http://www.nature.com/nature/journal/v548/n7667/full/nature23476.html 图片来源

【古生物】New gliding mammaliaforms from the Jurassic


Zhe-Xi Luo(罗哲西,芝加哥大学)et al.







(导读 寒雨)中生代哺乳形类为哺乳动物的早期演化提供了关键的化石证据。研究者在中国侏罗纪髫髻山组新发现了一种树栖性祖翼兽(Maiopatagium furculiferum),其独特的滑翔能力得益于翼膜、融合的叉骨及特殊的肩带,成为了哺乳动物进化史中最早的滑翔者。

Stem mammaliaforms are Mesozoic forerunners to mammals, and they offer critical evidence for the anatomical evolution and ecological diversification during the earliest mammalian history. Two new eleutherodonts from the Late Jurassic period have skin membranes and skeletal features that are adapted for gliding. Characteristics of their digits provide evidence of roosting behaviour, as in dermopterans and bats, and their feet have a calcaneal calcar to support the uropagatium as in bats. The new volant taxa are phylogenetically nested with arboreal eleutherodonts. Together, they show an evolutionary experimentation similar to the iterative evolutions of gliders within arboreal groups of marsupial and placental mammals. However, gliding eleutherodonts possess rigid interclavicle–clavicle structures, convergent to the avian furculum, and they retain shoulder girdle plesiomorphies of mammaliaforms and monotremes. Forelimb mobility required by gliding occurs at the acromion–clavicle and glenohumeral joints, is different from and convergent to the shoulder mobility at the pivotal clavicle–sternal joint in marsupial and placental gliders.


【生物】Integrative clinical genomics of metastatic cancer


Arul M. Chinnaiyan et al.



(导读 卓思琪)和原位癌相比,临床上对转移癌的分子分析尚不深入。本文对500名成年病人的不同类型转移性实体瘤进行了全外显子组和全转录组测序。实验中12.2%的病例存在生殖系可能致病突变,其中75%与DNA修复缺陷有关。RNA序列信息可以补足DNA序列信息,为基因融合、通路活性及免疫状况等提供信息,综合测序分析为复杂分子图景以及转移癌微环境的观测提供了一个多维的临床视图。


Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.


3 【物理】Ram-pressure feeding of supermassive black holes


Bianca M. Poggianti et al.






(导读 阿金)星系中心的超大质量黑洞吸积物质后会产生高能活动星系核(active galactic nucleus , AGN)。本研究对7个水母星系(具有气体“触手”)进行观测,发现其中6个具有AGN。研究人员分析指出,使气体从这些星系中剥离的冲撞压力也可能导致气体流向中心,为黑洞提供养料,触发AGN活动。


When a supermassive black hole at the centre of a galaxy accretes matter, it gives rise to a highly energetic phenomenon: an active galactic nucleus. Numerous physical processes have been proposed to account for the funnelling of gas towards the galactic centre to feed the black hole. There are also several physical processes that can remove gas from a galaxy, one of which is ram-pressure stripping by the hot gas that fills the space between galaxies in galaxy clusters. Here we report that six out of a sample of seven ‘jellyfish’ galaxies—galaxies with long ‘tentacles’ of material that extend for dozens of kiloparsecs beyond the galactic disks—host an active nucleus, and two of them also have galactic-scale ionization cones. The high incidence of nuclear activity among heavily stripped jellyfish galaxies may be due to ram pressure causing gas to flow towards the centre and triggering the activity, or to an enhancement of the stripping caused by energy injection from the active nucleus, or both. Our analysis of the galactic position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another possible mechanism for feeding the central supermassive black hole with gas.



4【物理】Vigorous atmospheric motion in the red supergiant star Antares


K. Ohnaka et al.



(导读 阿金)作为恒星演化最后阶段的红超巨星拥有复杂且多层的大气。本研究根据近红外光谱干涉成像数据,绘制了红超巨星心宿二Antares表面和周围大气的速度场分布图。该图显示出在延伸至1.7个恒星半径的Antares大气中,气团发生剧烈的运动,速度在-20 km/s20 km/s的范围之间。该运动无法仅通过大气对流进行解释,具体机制尚不明确。

 Red supergiant stars represent a late stage of the evolution of stars more massive than about nine solar masses, in which they develop complex, multi-component atmospheres. Bright spots have been detected in the atmosphere of red supergiants using interferometric imaging. Above the photosphere of a red supergiant, the molecular outer atmosphere extends up to about two stellar radii. Furthermore, the hot chromosphere (5,000 to 8,000 kelvin) and cool gas (less than 3,500 kelvin) of a red supergiant coexist at about three stellar radii. The dynamics of such complex atmospheres has been probed by ultraviolet and optical spectroscopy. The most direct approach, however, is to measure the velocity of gas at each position over the image of stars as in observations of the Sun. Here we report the mapping of the velocity field over the surface and atmosphere of the nearby red supergiant Antares. The two-dimensional velocity field map obtained from our near-infrared spectro-interferometric imaging reveals vigorous upwelling and downdrafting motions of several huge gas clumps at velocities ranging from about -20 to +20 kilometres per second in the atmosphere, which extends out to about 1.7 stellar radii. Convection alone cannot explain the observed turbulent motions and atmospheric extension, suggesting that an unidentified process is operating in the extended atmosphere.


5 【物理/材料】Electronic in-plane symmetry breaking at field-tuned quantum criticality in CeRhIn5


P. J. W. Moll et al.



(导读 阿金)电子向列相出现在铜基和铁基的高温超导体中,但对超导的影响尚且未知。本研究揭示,在50T的反铁磁量子相变点附近,重费米子超导体材料CeRhIn5中出现电子向列相。在排除了对称性破缺的其他来源后,研究人员认为超导与电子向列相之间存在某种关联。


Electronic nematic materials are characterized by a lowered symmetry of the electronic system compared to the underlying lattice, in analogy to the directional alignmen without translational order in nematic liquid crystals. Such nematic phases appear in the copper- and iron-based high-temperature superconductors, and their role in establishing superconductivity remains an open question. Nematicity may take an active part, cooperating or competing with superconductivity, or may appear accidentally in such systems. Here we present experimental evidence for a phase of fluctuating nematic character in a heavy-fermion superconductor, CeRhIn5 (ref. 5). We observe a magnetic-field-induced state in the vicinity of a field-tuned antiferromagnetic quantum critical point at Hc  50 tesla. This phase appears above an out-of-plane critical field H*  28 tesla and is characterized by a substantial in-plane resistivity anisotropy in the presence of a small in-plane field component. The in-plane symmetry breaking has little apparent connection to the underlying lattice, as evidenced by the small magnitude of the magnetostriction anomaly

at H*. Furthermore, no anomalies appear in the magnetic torque, suggesting the absence of metamagnetism in this field range. The appearance of nematic behaviour in a prototypical heavy-fermion superconductor highlights the interrelation of nematicity and unconventional superconductivity, suggesting nematicity to be common among correlated materials.



6【材料】Chaotic dynamics in nanoscale NbO2 Mott memristors for analogue computing

纳米级别的二氧化铌Mott 忆阻器中的混沌动力学

Suhas Kumar, R. Stanley Williams et al.



(导读 阿金)机器学习系统使用的神经元模型在混沌边缘模式中运行时可提高计算的复杂度,是计算系统的重要组成。本研究将单个尺寸小于100纳米的NbO2 Mott忆阻器结合到弛豫振荡器中,展示非线性电流传输和纳米尺度的热波动耦合可产生混沌振荡。将这种忆阻器并入Hopfield计算网络可大幅度提高计算效率和准确性。

At present, machine learning systems use simplified neuron models that lack the rich nonlinear phenomena observed in biological systems, which display spatio-temporal cooperative dynamics. There is evidence that neurons operate in a regime called the edge of chaos that may be central to complexity, learning efficiency, adaptability and analogue (non-Boolean) computation in brains. Neural networks have exhibited enhanced computational complexity when operated at the edge of chaos, and networks of chaotic elements have been proposed for solving combinatorial or global optimization problems8. Thus, a source of controllable chaotic behaviour that can be incorporated into a neural-inspired circuit may be an essential component of future computational systems. Such chaotic elements have been simulated using elaborate transistor circuits that simulate known equations of chaos, but an experimental realization of chaotic dynamics from a single scalable electronic device has been lacking. Here we describe niobium dioxide (NbO2) Mott memristors each less than 100 nanometres across that exhibit both a nonlinear-transport-driven current-controlled negative differential resistance and a Mott-transition-driven temperature-controlled negative differential resistance. Mott materials have a temperature-dependent metal–insulator transition that acts as an electronic switch, which introduces a history-dependent resistance into the device. We incorporate these memristors into a relaxation oscillator and observe a tunable range of periodic and chaotic self-oscillations. We show that the nonlinear current transport coupled with thermal fluctuations at the nanoscale generates chaotic oscillations. Such memristors could be useful in certain types of neural-inspired computation by introducing a pseudo-random signal that prevents global synchronization and could also assist in finding a global minimum during a constrained search. We specifically demonstrate that incorporating such memristors into the hardware of a Hopfield computing network can greatly improve the efficiency and accuracy of converging to a solution for computationally difficult problems.



7【考古】An early modern human presence in Sumatra 7300063000 years ago


K. E. Westaway et al.



(导读:阿金)遗传信息显示晚期智(AMH)7.5万年前离开非洲后约在6万年前抵达东南亚诸岛,但尚缺乏相应考古记录。本研究重新分析了苏门答腊岛上Lida Ajer岩洞内牙齿化石的釉质厚度和形态,并使用冷发光、耦合铀衰变和电子自旋震荡技术测得其年龄为7.3万至6.3万年,给出6万年前东南亚已有AMH生活的新证据。

Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93–61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a   lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications 分类鉴定. Lida Ajer is a Sumatran Pleistocene cave 更新世岩洞 with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel–dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA2. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.


8【古生物】New evidence for mammaliaform ear evolution and feeding adaptation in a Jurassic ecosystem


Zhe-Xi Luo(罗哲西,芝加哥大学), Qing-Jin Meng(孟庆金,北京自然博物馆)et al.









(导读 寒雨)中生代哺乳形类为哺乳动物的早期演化提供了关键的化石证据。本研究描述了中国侏罗纪髫髻山组双钵翔齿兽(Vilevolodon diplomylos)化石的耳部和牙齿结构及牙齿替换模式,推测其为食草动物,为了解被子植物和滑翔类哺乳形动物之间的关系提供了新见解。

Stem mammaliaforms are forerunners to modern mammals1, and they achieved considerable ecomorphological diversity in their own right2. Recent discoveries suggest that eleutherodontids, a subclade of Haramiyida, were more species-rich during the Jurassic period in Asia than previously recognized3, 4, 5, 6, 7, 8, 9, 10, 11, 12. Here we report a new Jurassic eleutherodontid mammaliaform with an unusual mosaic of highly specialized characteristics1, 2, 3, 4, 5, 6, and the results of phylogenetic analyses that support the hypothesis that haramiyidans are stem mammaliaforms. The new fossil shows fossilized skin membranes that are interpreted to be for gliding and a mandibular middle ear with a unique character combination previously unknown in mammaliaforms. Incisor replacement is prolonged until well after molars are fully erupted, a timing pattern unique to most other mammaliaforms. In situ molar occlusion and a functional analysis reveal a new mode of dental occlusion: dual mortar–pestle occlusion of opposing upper and lower molars, probably for dual crushing and grinding. This suggests that eleutherodontids are herbivorous, and probably specialized for granivory or feeding on soft plant tissues. The inferred dietary adaptation of eleutherodontid gliders represents a remarkable evolutionary convergence with herbivorous gliders in Theria. These Jurassic fossils represent volant, herbivorous stem mammaliaforms associated with pre-angiosperm plants that appear long before the later, iterative associations between angiosperm plants and volant herbivores in various therian clades.


9【生物】Rewiring the taste system


Charles S. Zuker et al.







In mammals, taste buds typically contain 50–100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami1, 2. Notably, mature taste cells have life spans of only 5–20 days and, consequently, are constantly replenished by differentiation of taste stem cells3. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A)4, 5, 6. We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.

(导读 谭坤)味觉受体细胞(TRC)每 5~20 天就会更新一次,需要和相关的外周神经节重新建立正确的连接。本研究发现甜味和苦味TRC经由SEMA3ASEMA7A分子来引导连接形成,并通过基因工程改变TRC产生的分子类型生成了错误的连接,从而揭示了味觉系统神经连接的奥秘。


10 【生物】Correction of aberrant growth preserves tissue homeostasis


Slobodan Beronja, Valentina Greco et al.



(导读 寒雨)组织在突变细胞的存在下如何保持正常表型仍不得而知。学者用活体成像技术研究带有活化Wnt /β-连环蛋白干细胞的小鼠皮肤上皮组织,发现所有导致皮肤组织结构变形的生长都会消退。揭示了成熟皮肤上皮的可塑性和维持稳态的动态细胞行为。


Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes1, 2, 3. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/β-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.


11 【生物】m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

m6A mRNA甲基化通过靶向IL-7 / STAT5 / SOCS途径调控T细胞体内平衡

Hua-Bing Li(李华兵,上海交通大学), Zhinan Yin(尹芝南,暨南大学), Richard A. Flavell et al.



(导读 寒雨)m6A在哺乳动物体内的生理功能尚不清楚。本研究发现,敲除小鼠T细胞中的m6A修饰酶METTL3可破坏其稳态和分化,且m6A的缺失可增加SOCS家族活性,从而抑制IL-7应答通路。首次揭示了m6A修饰在T细胞稳态维持及分化功能中的重要作用和调控T细胞稳态增殖的分子机制。


N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark1, 2. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates3, 4. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.


12【生物】Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood


Eric S. Lander, Feng Zhang(张锋,MIT et al.



Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.


(导读 郭怿暄)哺乳动物基因组中存在数以千计的长非编码RNAslncRNAs)位点,本研究利用CRISPR-Cas9系统开发出一种以lncRNA为靶向的基因组范围的激活筛选方法,在人类黑色素瘤细胞中发现介导BRAF抑制剂抵抗的11lncRNA位点,其中EMICERI的激活可以调节附近4个编码蛋白质的基因表达。这一全新方法为系统地研究非编码区功能及调节机制奠定了基础。



13【生物】mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome

mRNA 3′ 尿苷化和Poly(A)尾巴长度塑造了哺乳动物母源细胞转录组

Dónal O’Carroll et al.



A fundamental principle in biology is that the program for early development is established during oogenesis in the form of the maternal transcriptome. How the maternal transcriptome acquires the appropriate content and dosage of transcripts is not fully understood. Here we show that 3′ terminal uridylation of mRNA mediated by TUT4 and TUT7 sculpts the mouse maternal transcriptome by eliminating transcripts during oocyte growth. Uridylation mediated by TUT4 and TUT7 is essential for both oocyte maturation and fertility. In comparison to somatic cells, the oocyte transcriptome has a shorter poly(A) tail and a higher relative proportion of terminal oligo-uridylation. Deletion of TUT4 and TUT7 leads to the accumulation of a cohort of transcripts with a high frequency of very short poly(A) tails, and a loss of 3′ oligo-uridylation. By contrast, deficiency of TUT4 and TUT7 does not alter gene expression in a variety of somatic cells. In summary, we show that poly(A) tail length and 3′ terminal uridylation have essential and specific functions in shaping a functional maternal transcriptome.


(导读 郭怿暄)卵细胞发生过程中建立起的母源转录组对胚胎发育至关重要。本研究发现由TUT4TUT7可以对mRNA 3’末端进行尿苷化修饰,从而在卵细胞生长过程中通过调控转录本的降解来塑造母源转录组。删除这两个蛋白后,拥有极短poly(A)尾巴的转录本在卵细胞中特异性增多并失去3’端尿苷化修饰,严重影响了卵细胞的成熟和动物的生育能力。


14 【生物】Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3


Tom A. Rapoport, Maofu Liao et al.



Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasomea pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain. Hrd1 is the crucial membrane component for retro-translocation, but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite directionfrom the cytosol into or across membranes. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.


(导读 吴媛媛)内质网相关蛋白降解(ERAD)是内质网膜或腔体中错误折叠蛋白的降解途径,泛素连接酶Hrd1是酵母中该信号途径的重要组分,但Hrd1能否形成蛋白输出通道尚不清楚。本文报道了Hrd1结合内质网腔蛋白Hrd3形成的复合物的冷冻电镜结构,证实了Hrd1可形成内质网错误折叠蛋白的逆向转运通道。



15【生物】Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6


Junken Aoki, Osamu Nureki et al.



Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1LPA3)1 and the phylogenetically distant non-EDG family (LPA4LPA6)4. The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.

(导读 吴媛媛)溶血磷脂酸(LPA)可激活G蛋白偶联受体并引起多种细胞反应,是癌症和纤维化病变的理想药物靶点。目前LPA受体中非内皮细胞分化基因(non-EDG)家族的功能和药理学特性尚不清楚。本文报道了该家族中LPA6的蛋白结构,并综合结构分析和突变实验探讨了其与LPA的结合模式,分析发现该受体构象重排被后激活。