
SCARF1は修飾LDLを認識し、結合するための重要な部位を持つ。SCARF1は二量体を形成し、この二量体構造が脂質タンパク質との結合に重要な役割を果たす。


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SCARF1 (Scavenger receptor class F member 1, SREC-1 or SR-F1) is a type I transmembrane protein that recognizes multiple endogenous and exogenous ligands such as modified low-density lipoproteins (LDL) and is important for maintaining homeostasis and immunity. But the structural information and the mechanisms of ligand recognition of SCARF1 are largely unavailable. Here we solve the crystal structures of the N-terminal fragments of human SCARF1, which show that SCARF1 forms homodimers and its epidermal growth factor (EGF)-like domains adopt a long-curved conformation. Then we examine the interactions of SCARF1 with lipoproteins and are able to identify a region on SCARF1 for recognizing modified LDLs. The mutagenesis data show that the positively charged residues in the region are crucial for the interaction of SCARF1 with modified LDLs, which is confirmed by making chimeric molecules of SCARF1 and SCARF2. In addition, teichoic acids, a cell wall polymer expressed on the surface of gram-positive bacteria, are able to inhibit the interactions of modified LDLs with SCARF1, suggesting the ligand binding sites of SCARF1 might be shared for some of its scavenging targets. Overall, these results provide mechanistic insights into SCARF1 and its interactions with the ligands, which are important for understanding its physiological roles in homeostasis and the related diseases.

### Competing Interest Statement

The authors have declared no competing interest.

Structure of scavenger receptor SCARF1 and its interaction with lipoproteins

scarf1の構造と脂質タンパク質との相互作用の解明


SCARF1の構造と脂質タンパク質との相互作用の解明


title_rewrite


GAT1 輸送体は、GABA の再取り込みを Na+ および Cl- イオンの共輸送によって行う。Na+ イオンの結合は、GAT1 の構造と機能を安定化させ、GABA 取り込みを促進する。


The human GABA transporter (GAT1) is a membrane transporter that mediates the reuptake of the neurotransmitter GABA from the synaptic cleft into neurons and glial cells. Dysregulation of the transport cycle has been associated with epilepsy and neuropsychiatric disorders, highlighting the crucial role of the transporter in maintaining homeostasis of brain GABA levels. GAT1 is a secondary active transporter that couples the movement of substrate to the simultaneous transport of sodium and chloride ions along their electrochemical gradients. Using MD simulations, we identified a novel sodium recruiting site at the entrance to the outer vestibule, which attracts positively charged ions and increases the local sodium concentration, thereby indirectly increasing sodium affinity. Mutations of negatively charged residues at the recruiting site slowed the binding kinetics, while experimental data revealed a change in sodium dependency of GABA uptake and a reduction of sodium affinity. Simulation showed that sodium displays a higher affinity for the sodium binding site NA2, which plays a role in stabilisation of the outward-open conformation. We directly show that the presence of a sodium ion bound to NA2 increases the stability of the closed inner gate and restrains motions of TM5. We find that sodium is only weakly bound to NA1 in the absence of GABA, while the presence of the substrate strengthens the interaction due to the completed ion coordinating shell, explaining cooperativity between GABA and sodium.

### Competing Interest Statement

The authors have declared no competing interest.

Interaction of GAT1 with sodium ions: from efficient recruitment to stabilisation of substrate and conformation

gat1-輸送体における-na-イオンの相互作用-効率的な取り込みから基質および構造の安定化まで


GAT1 輸送体における Na+ イオンの相互作用：効率的な取り込みから基質および構造の安定化まで



蛋白質配列データと発現レベルを統合することで、乳がんサブタイプの分子特性を明らかにし、臨床転帰を予測することができる。


乳がんサブタイプの分子特性解析のための蛋白質配列とその発現レベルの統合


オビダクトは、精子や胚の存在に応じて時空間的に遺伝子発現とタンパク質産生を動的に変化させる適応的な器官である。


The oviduct is the site of fertilization and preimplantation embryo development in mammals. Evidence suggests that gametes alter oviductal gene expression. To delineate the adaptive interactions between the oviduct and gamete/embryo, we performed a multi-omics characterization of oviductal tissues utilizing bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and proteomics collected from distal and proximal at various stages after mating in mice. We observed robust region-specific transcriptional signatures. Specifically, the presence of sperm induces genes involved in pro-inflammatory responses in the proximal region at 0.5 days post-coitus (dpc). Genes involved in inflammatory responses were produced specifically by secretory epithelial cells in the oviduct. At 1.5 and 2.5 dpc, genes involved in pyruvate and glycolysis were enriched in the proximal region, potentially providing metabolic support for developing embryos. Abundant proteins in the oviductal fluid were differentially observed between naturally fertilized and superovulated samples. RNA-seq data were used to identify transcription factors predicted to influence protein abundance in the proteomic data via a novel machine learning model based on transformers of integrating transcriptomics and proteomics data. The transformers identified influential transcription factors and correlated predictive protein expressions in alignment with the in vivo -derived data. In conclusion, our multi-omics characterization and subsequent in vivo confirmation of proteins/RNAs indicate that the oviduct is adaptive and responsive to the presence of sperm and embryos in a spatiotemporal manner.

Significance Statement We conducted a detailed molecular study of how the oviduct changes its gene expression and protein production in response to sperm and embryos after mating in mice. We found that the oviduct has distinct molecular signatures in different regions - upper versus lower regions. Shortly after mating, inflammatory responses are turned on in the lower regions due to the presence of sperm. A bit later, metabolic genes ramp up in the lower regions, likely to provide nutrients for the developing embryos. Overall, this multi-omics study revealed the oviduct dynamically adapts its molecular makeup over time and space to accommodate and support sperm, eggs and embryos.

### Competing Interest Statement

The authors have declared no competing interest.

Multi-omics analyses and machine learning prediction of oviductal responses in the presence of gametes and embryos

自然受精時のオビダクトの反応を多オミクス解析とマシンラーニング予測で明らかにする


生物医学時系列データの変化点分析のために、一般化線形混合効果モデルを開発した。このモデルは、生物医学時系列データに通常存在する構造を取り入れることができる。


生物医学時系列データの変化点分析のための一般化線形混合効果モデル


マグネトソームの異なる形状が、温度変化に伴う磁気特性の変化に大きな影響を及ぼすことが明らかになった。特に、低温域での磁気異方性の複雑な変化が、マグネトソームの優れた磁気特性を生み出している。


磁性細菌のマグネトソームにおける異方性の複雑な相互作用の探索


単一細胞RNA配列データの可視化において、データの不確実性を考慮することで、より正確な細胞集団の構造を捉えることができる。


単一細胞rna配列データの不確実性を考慮したt-sneによる可視化


単一細胞RNA配列データの不確実性を考慮したt-SNEによる可視化



LYCHOSはコレステロール依存的にmTORC1を活性化する細胞内コレステロールセンサーである。その構造はプラントのオーキシントランスポーターと哺乳類のGPCRドメインを融合した特殊な膜タンパク質である。


Cryo-electron microscopy structures of the human lysosomal transmembrane protein LYCHOS show that it comprises a transporter-like domain fused to a G-protein-coupled receptor, and that the transporter domain is similar to the plant PIN family.

LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR - Nature

人間とプラントのpinトランスポーターとgpcrのハイブリッドであるlychos


人間とプラントのPINトランスポーターとGPCRのハイブリッドであるLYCHOS



WNKキナーゼは、水分子ネットワークと塩化物イオン結合部位の変化によって、不活性二量体から活性モノマーへの転換を制御されている。


Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1and CWN2). Here we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride binding site and are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 Cluster mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.

### Competing Interest Statement

The authors have declared no competing interest.

Water and chloride as allosteric inhibitors in WNK kinase osmosensing

wnkキナーゼの浸透圧センシングにおける水とクロリドの協調的な阻害作用


WNKキナーゼの浸透圧センシングにおける水とクロリドの協調的な阻害作用



地面での自己起立には、重力ポテンシャルエネルギーの障壁を乗り越えるために機械的エネルギーを生み出す必要がある。この物理的制約が、動物の行動戦略や3次元の体の回転に影響を及ぼす。


地面での自己起立に関する物理原理の最近の進展