1 RNA phase transitions in repeat expansion disorders 【生物】重骈前言列扩张相干疾病中的 RNA相变 Ankur Jain Ronald D. Vale https://www.nature.com/nature/journal/v546/n7657/full/nature22386.html （带读 郭怿暄）基因组中
1 RNA phase transitions in repeat expansion disorders
Ankur Jain & Ronald D. Vale
Expansions of short nucleotide repeats produce several neurological and neuromuscular disorders including Huntington disease, muscular dystrophy, and amyotrophic lateral sclerosis. A common pathological feature of these diseases is the accumulation of the repeat-containing transcripts into aberrant foci in the nucleus. RNA foci, as well as the disease symptoms, only manifest above a critical number of nucleotide repeats, but the molecular mechanism governing foci formation above this characteristic threshold remains unresolved. Here we show that repeat expansions create templates for multivalent base-pairing, which causes purified RNA to undergo a sol–gel transition in vitro at a similar critical repeat number as observed in the diseases. In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Analogous to protein aggregation disorders, our results suggest that the sequence-specific gelation of RNAs could be a contributing factor to neurological disease.
2 Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein
Yan Zhang, Bingfa Sun, Dan Feng…Brian K. Kobilka & Georgios Skiniotis
(带读：阿金) GLP-1却以调理胰岛斋的分泌，把持新老代谢以及按捺食欲，什分拥有助于糖尿病的治水疗。GLP-1受体属于B类G蛋清偶联受体（GRCP），条是关于记号转带机制的了松依然拥有囿于性。近日到，迷信家经度过冷冻结电镜技术松析了活募化的GLP-1R–Gs 骈合物的近原儿子分辨比值图。该项切磋结实为进壹步了松B类GPCR的工干规律,以及不到来的药物开辟工干供了要紧的线索。
Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion，carbohydrate 365bet最新网址lism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor,a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the 365bet最新网址 of transmembrane helix, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.
3 Crystal structure of the GLP-1 receptor bound to a peptide agonist
Ali Jazayeri, Mathieu Rappas, Alastair J. H. Brown…Robert M. Cooke & Fiona H. Marshall
Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.
4 Structure of the full-length glucagon class B G-protein-coupled receptor
Haonan Zhang, Anna Qiao, Dehua Yang…Hualiang Jiang, Ming-Wei Wang & Beili Wu（蒋华良、王皓伟、吴蓓丽，上海药物所）
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen–deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
5 Discovery of intrinsic ferromagnetism in two-365bet最新网址al van der Waals crystals
Cheng Gong, Lin Li, Zhenglu Li…Jing Xia & Xiang Zhang(张翔,UC Berkeley)
(带读 王腾) 二维分儿子晶体若能完长程铁磁拥有前言，又结合优秀的电学和光学干用，便却在磁性、磁电和磁光范畴父亲殿经纶。本切磋借助扫描磁光克尔露微镜提示了Cr2Ge2Te6 （接近雄心的二维Heisenberg铁磁体）原儿子层中本征长程铁磁拥有前言性。切磋人员使用极小的磁场（＜0.3T），初次完成对该材料转变温度（铁磁恭顺磁性样儿子间）的把持。该发皓拥有助于切磋根本的己旋行为，对超集儿子成型己旋电儿子学等新范畴具拥有要紧意思。
The realization of long-range ferromagnetic order in two-365bet最新网址al van der Waals crystals, combined with their rich electronic and optical properties, could lead to new magnetic, magnetoelectric and magneto-optic 365bet最新网址1, 2, 3, 4. In two-365bet最新网址al systems, the long-range magnetic order is strongly suppressed by thermal fluctuations, according to the Mermin–Wagner theorem5; however, these thermal fluctuations can be counteracted by magnetic anisotropy. Previous efforts, based on defect and composition engineering6, 7, 8, 9, 10, or the proximity effect, introduced magnetic responses only locally or extrinsically. Here we report intrinsic long-range ferromagnetic order in pristine Cr2Ge2Te6 atomic layers, as revealed by scanning magneto-optic Kerr microscopy. In this magnetically soft, two-365bet最新网址al van der Waals ferromagnet, we achieve unprecedented control of the transition temperature (between ferromagnetic and paramagnetic states) using very small fields (smaller than 0.3 tesla). This result is in contrast to the insensitivity of the transition temperature to magnetic fields in the three-365bet最新网址al regime. We found that the small applied field leads to an effective anisotropy that is much greater than the near-zero magnetocrystalline anisotropy, opening up a large spin-wave excitation gap. We explain the observed phenomenon using renormalized spin-wave theory and conclude that the unusual field dependence of the transition temperature is a hallmark of soft, two-365bet最新网址al ferromagnetic van der Waals crystals. Cr2Ge2Te6 is a nearly ideal two-365bet最新网址al Heisenberg ferromagnet and so will be useful for studying fundamental spin behaviours, opening the door to exploring new 365bet最新网址 such as ultra-compact spintronics.
6 Layer-dependent ferromagnetism in a van der Waals crystal down to the monolayer limit
Bevin Huang, Genevieve Clark, Efrén Navarro-Moratalla…Pablo Jarillo-Herrero & Xiaodong Xu（许晓栋，华盛顿父亲学正西雅图分校）
(带读 田莉）具拥有内在磁性的二维晶体却被运用于在好多技术中（从传感触数据存放储），但此雕刻类晶体能否存放在依然不知。本切磋使用磁光克尔效应露微镜证皓了单层叁碘募化铬(CrI3)二维材料为伊辛铁磁体，其居里温度为45 k，但微低于块状材料（61 k）。切磋还提出产了壹个依顶赖于分儿子层数的磁态相，突露出产范道德瓦尔斯晶体中典型的厚度依顶赖物理习惯。
Since the discovery of graphene1, the family of two-365bet最新网址al materials has grown, displaying a broad range of electronic properties. Recent additions include semi365bet最新网址 with spin–valley coupling2, Ising super365bet最新网址3, 4, 5 that can be tuned into a quantum metal6, possible Mott insulators with tunable charge-density waves7, and topological semimetals with edge transport8, 9. However, no two-365bet最新网址al crystal with intrinsic magnetism has yet been discovered10, 11, 12, 13, 14; such a crystal would be useful in many technologies from sensing to data storage15. Theoretically, magnetic order is prohibited in the two-365bet最新网址al isotropic Heisenberg model at finite temperatures by the Mermin–Wagner theorem16. Magnetic anisotropy removes this restriction, however, and enables, for instance, the occurrence of two-365bet最新网址al Ising ferromagnetism. Here we use magneto-optical Kerr effect microscopy to demonstrate that monolayer chromium triiodide (CrI3) is an Ising ferromagnet with out-of-plane spin orientation. Its Curie temperature of 45?kelvin is only slightly lower than that of the bulk crystal, 61?kelvin, which is consistent with a weak interlayer coupling. Moreover, our studies suggest a layer-dependent magnetic phase, highlighting thickness-dependent physical properties typical of van der Waals crystals17, 18,19. Remarkably, bilayer CrI3 displays suppressed magnetization with a metamagnetic effect20, whereas in trilayer CrI3 the interlayer ferromagnetism observed in the bulk crystal is restored. This work creates opportunities for studying magnetism by harnessing the unusual features of atomically thin materials, such as electrical control for realizing magnetoelectronics12, and van der Waals engineering to produce interface phenomena15.
7 Microresonator-based solitons for massively parallel coherent optical communications
Pablo Marin-Palomo, Juned N. Kemal, Maxim Karpov ，Arne Kordts, Joerg Pfeifle, Martin H. P. Pfeiffer, Philipp Trocha, Stefan Wolf, Victor Brasch, Miles H. Anderson, Ralf Rosenberger, Kovendhan Vijayan, Wolfgang Freude, Tobias J. Kippenberg & Christian Koo
Affiliation: Institute of Photonics and Quantum Electronics (IPQ), Karlsruhe Institute of Technology (KIT), Laboratory of Photonics and Quantum Measurements (LPQM), école Polytechnique Fédérale de Lausanne (EPFL), Institute of Microstructure Technology (IMT), Karlsruhe Institute of Technology (KIT)
Solitons are waveforms that preserve their shape while propagating, as a result of a balance of dispersion and nonlinearity1, 2. Soliton-based data transmission schemes were investigated in the 1980s and showed promise as a way of overcoming the limitations imposed by dispersion of optical fibres. However, these approaches were later abandoned in favour of wavelength-division multiplexing schemes, which are easier to implement and offer improved scalability to higher data rates. Here we show that solitons could make a comeback in optical communications, not as a competitor but as a key element of massively parallel wavelength-division multiplexing. Instead of encoding data on the soliton pulse train itself, we use continuous-wave tones of the associated frequency comb as carriers for communication. Dissipative Kerr solitons (DKSs)3, 4 (solitons that rely on a double balance of parametric gain and cavity loss, as well as dispersion and nonlinearity) are generated as continuously circulating pulses in an integrated silicon nitride microresonator5 via four-photon interactions mediated by the Kerr nonlinearity, leading to low-noise, spectrally smooth, broadband optical frequency combs6. We use two interleaved DKS frequency combs to transmit a data stream of more than 50 terabits per second on 179 individual optical carriers that span the entire telecommunication C and L bands (centred around infrared telecommunication wavelengths of 1.55 micrometres). We also demonstrate coherent detection of a wavelength-division multiplexing data stream by using a pair of DKS frequency combs—one as a multi-wavelength light source at the transmitter and the other as the corresponding local oscillator at the receiver. This approach exploits the scalability of microresonator-based DKS frequency comb sources for massively parallel optical communications at both the transmitter and the receiver. Our results demonstrate the potential of these sources to replace the arrays of continuous-wave lasers that are currently used in high-speed communications. In combination with advanced spatial multiplexing schemes7, 8 and highly integrated silicon photonic circuits9, DKS frequency combs could bring chip-scale petabit-per-second transceivers into reach.
8 Accelerated discovery of two crystal structure types in a complex inorganic phase field
C. Collins, M. S. Dyer, M. J. Pitcher…G. R. Darling & M. J. Rosseinsky
The discovery of new materials is hampered by the lack of efficient approaches to the exploration of both the large number of possible elemental compositions for such materials, and of the candidate structures at each composition. For example, the discovery of inorganic extended solid structures has relied on knowledge of crystal chemistry coupled with time-consuming materials synthesis with systematically varied elemental ratios. Computational methods have been developed to guide synthesis by predicting structures at specific compositions and predicting compositions for known crystal structures, with notable successes. However, the challenge of finding qualitatively new, experimentally realizable compounds, with crystal structures where the unit cell and the atom positions within it differ from known structures, remains for compositionally complex systems. Many valuable properties arise from substitution into known crystal structures, but materials discovery using this approach alone risks both missing best-in-class performance and attempting design with incomplete knowledge. Here we report the experimental discovery of two structure types by computational identification of the region of a complex inorganic phase field that contains them. This is achieved by computing probe structures that capture the chemical and structural diversity of the system and whose energies can be ranked against combinations of currently known materials. Subsequent experimental exploration of the lowest-energy regions of the computed phase diagram affords two materials with previously unreported crystal structures featuring unusual structural motifs. This approach will accelerate the systematic discovery of new materials in complex compositional spaces by efficiently guiding synthesis and enhancing the predictive power of the computational tools through expansion of the knowledge base underpinning them.
9 Frequency dependence limits divergent evolution by favouring rare immigrants over residents
Daniel I. Bolnick & William E. Stutz
Two distinct forms of natural selection promote adaptive biological diversity. Divergent selection occurs when different environments favour different phenotypes, leading to increased differences between populations1. Negative frequency-dependent selection occurs when rare variants within a population are favoured over common ones2, increasing diversity within populations3. These two diversifying forces promote genetic variation at different spatial scales, and may act in opposition, but their relative effects remain unclear because they are rarely measured concurrently. Here we show that negative frequency-dependent selection within populations can favor rare immigrants over locally adapted residents. We reciprocally transplanted lake and stream ecotypes of threespine stickleback4 into lake and stream habitats, while manipulating the relative abundance of residents versus immigrants. We found negative frequency-dependence: survival was highest for the locally rare ecotype, rather than natives. Also, individuals with locally rare major histocompatibility complex (MHC) class IIb genotypes were infected by fewer parasites. This negative frequency-dependent selection will tend to favour rare immigrants over common residents, amplifying the effect of migration and undermining the efficacy of divergent natural selection to drive population differences. The only signal of divergent selection was a tendency for foreign fish to have higher parasite loads than residents, after controlling for MHC genotype rarity. Frequency-dependent ecological interactions have long been thought to promote speciation. Our results suggest a more nuanced view in which negative frequency dependence alters the fate of migrants to promote or constrain evolutionary divergence between populations.
10 New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens
Jean-Jacques Hublin, Abdelouahed Ben-Ncer, Shara E. Bailey…Katerina Harvati & Philipp Gunz
（带读 刘威尔）当代当世智人样儿子特点是迅快结合还是逐步演募化尚不皓白。本切磋报道了在摩洛哥杰贝尔依罗（Jebel Irhoud）遗址发皓的人类募化石，其面部、下颌、牙齿样儿子与当代当近人类相近而脑颅和颅内样儿子较原始，暖和释光测年标注皓该遗址是最新鲜的匪洲中石器时代古人类遗址，它记载了具拥有当代当近人类关键样儿子的初期智人分顶，并标注皓智人演募化经过触及整顿个匪洲父亲陆。
Fossil evidence points to an African origin of Homo sapiens from a group called either H. heidelbergensis or H. rhodesiensis. However, the exact place and time of emergence of H. sapiens remain obscure because the fossil record is scarce and the chronological age of many key specimens remains uncertain. In particular, it is unclear whether the present day ‘modern’ morphology 365bet最新网址ly emerged approximately 200 thousand years ago (ka) among earlier r365bet最新网址esentatives of H. sapiens1 or evolved gradually over the last 400 thousand years2. Here we report newly discovered human fossils from Jebel Irhoud, Morocco, and interpret the affinities of the hominins from this site with other archaic and recent human groups. We identified a mosaic of features including facial, mandibular and dental morphology that aligns the Jebel Irhoud material with early or recent anatomically modern humans and more primitive neurocranial and endocranial morphology. In combination with an age of 315?±?34 thousand years (as determined by thermoluminescence dating)3, this evidence makes Jebel Irhoud the oldest and richest African 365bet最新网址 Stone Age hominin site that documents early stages of the H. sapiens clade in which key features of modern morphology were established. Furthermore, it shows that the evolutionary processes behind the emergence ofH. sapiensinvolved the whole African continent.
11 The age of the hominin fossils from Jebel Irhoud, Morocco, and the origins of the 365bet最新网址 Stone Age
Daniel Richter, Rainer Grün, Renaud Joannes-Boyau…Jean-Jacques Hublin & Shannon P. McPherron
The timing and location of the emergence of our species and of associated behavioural changes are crucial for our understanding of human evolution. The earliest fossil attributed to a modern form of Homo sapiens comes from eastern Africa and is approximately 195 thousand years old1, 2, therefore the emergence of modern human biology is commonly placed at around 200 thousand years ago3, 4. The earliest 365bet最新网址 Stone Age assemblages come from eastern and southern Africa but date much earlier5, 6, 7. Here we report the ages, determined by thermoluminescence dating, of fire-heated flint artefacts obtained from new excavations at the 365bet最新网址 Stone Age site of Jebel Irhoud, Morocco, which are directly associated with newly discovered remains of H. sapiens8. A weighted average age places these 365bet最新网址 Stone Age artefacts and fossils at 315?±?34 thousand years ago. Support is obtained through the recalculated uranium series with electron spin resonance date of 286?±?32 thousand years ago for a tooth from the Irhoud 3 hominin mandible. These ages are also consistent with the faunal and microfaunal9 assemblages and almost double the previous age estimates for the lower part of the deposits10, 11. The north African site of Jebel Irhoud contains one of the earliest directly dated 365bet最新网址 Stone Age assemblages, and its associated human remains are the oldest reported for H. sapiens. The emergence of our species and of the 365bet最新网址 Stone Age appear to be close in time, and these data suggest a larger scale, potentially pan-African, origin for both.
12 Dynamic corticostriatal activity biases social bonding in monogamous female prairie voles
Elizabeth A. Amadei, Zachary V. Johnson, Yong Jun Kwon…Larry J. Young & Robert C. Liu
（带读 刘威尔）社会联绕中触及到的父亲脑嘉奖品神物经机制尚不皓白。本切磋使用草原田鼠（Microtus ochrogaster）的匹偶结合模具标注皓，动态调理从内侧前额叶皮质到俯伏隔核的壹个干用邮路却以增强大雌性对匹偶的亲和行为。切磋结实提出产了社会相干结合经过中皮质活触动的动态不雅概念，提示了社会互触动伸发父亲脑嘉奖品机制并改触动亲和行为的机制。
Adult pair bonding involves dramatic changes in the perception and valuation of another individual1. One key change is that partners come to reliably activate the brain’s reward system2, 3, 4, 5, 6, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding7, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females’ affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit’s activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.
13 The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition
Gabriele Varano, Simon Raffel, Martina Sormani…Klaus Rajewsky & Stefano Casola
(带读 郭思瑶)B细胞抗原受体(BCR)记号传带能是肿瘤细胞长所必须的 。迷信家发皓BCR缺违反不影响淋巴癌细胞本身的长，但却在竞赛环境下处于不顺溜位置。BCR缺违反添加以了肿瘤细胞对营养限度局限的敏感度，增添以了糖原分松酶激酶3 β (GSK3β)活触动到来顶持MYC调控的基因表臻，进而削绵软弱了淋巴瘤细胞的顺应度。切磋标注皓BCR缺违反细胞或成药物治水疗新靶点。
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR?) tumour cells 365bet最新网址ly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon 365bet最新网址lism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR? tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR? lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually r365bet最新网址esent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR? tumour cells.
14 Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
Gaojie Song, Dehua Yang, Yuxia Wang…Ming-Wei Wang & Raymond C. Stevens
The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis1. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner2. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR3 and located outside helices V–VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs4, 5, 6. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.
15 Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signaling
Markus Brockmann, Vincent A. Blomen, Joppe Nieuwenhuis…Lucas T. Jae & Thijn R. Brummelkamp
As key executers of biological functions, the activity and abundance of proteins are subjected to extensive regulation. Deciphering the genetic architecture underlying this regulation is critical for understanding cellular signalling events and responses to environmental cues. Using random mutagenesis in haploid human cells, we apply a sensitive approach to directly couple genomic mutations to protein measurements in individual cells. Here we use this to examine a suite of cellular processes, such as transcriptional induction, regulation of protein abundance and splicing, signalling cascades (mitogen-activated protein kinase (MAPK), G-protein-coupled receptor (GPCR), protein kinase B (AKT), interferon, and Wingless and Int-related protein (WNT) pathways) and epigenetic modifications (histone crotonylation and methylation). This scalable, sequencing-based procedure elucidates the genetic landscapes that control protein states, identifying genes that cause very narrow phenotypic effects and genes that lead to broad phenotypic consequences. The resulting genetic wiring map identifies the E3-ligase substrate adaptor KCTD5 as a negative regulator of the AKT pathway, a key signalling cascade frequently deregulated in cancer. KCTD5-deficient cells show elevated levels of phospho-AKT at S473 that could not be attributed to effects on canonical pathway components. To reveal the genetic requirements for this phenotype, we iteratively 365bet最新网址 the regulatory network linked to AKT activity in the knockout background. This genetic modifier screen exposes suppressors of the KCTD5 phenotype and mechanistically demonstrates that KCTD5 acts as an off-switch for GPCR signalling by triggering proteolysis of Gβγ heterodimers dissociated from the Gα subunit. Although biological networks have previously been constructed on the basis of gene expression, protein–protein associations, or genetic interaction profiles, we foresee that the approach described here will enable the generation of a comprehensive genetic wiring map for human cells on the basis of quantitative protein states.