Article
Biology
Hristina R. R. Zhekova, Jiansen Jiang, Weiguang Wang, Kirill Tsirulnikov, Guelru Kayik, Hanif Muhammad Khan, Rustam Azimov, Natalia Abuladze, Liyo Kao, Debbie Newman, Sergei Yu. Noskov, D. Peter Tieleman, Z. Hong Zhou, Alexander Pushkin, Ira Kurtz
Summary: In this study, the cryoEM structures of both inward-facing and outward-facing conformations of a mammalian SLC4 family protein were determined. The inward-facing structures showed downward movement in the core domain and unexpected elongation of TM11.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xi Zhang, Cang Wu, Zhihong Song, Dayong Sun, Liting Zhai, Chuang Liu
Summary: In this study, the structures of full-length SORLA were determined and two distinct conformations of apo-SORLA were identified using single-particle cryogenic electron microscopy. Unlike homologous proteins, SORLA existed in both monomer and dimer forms in a neutral solution. Only three hydrogen bonds near the dimer interface were involved in dimerization, and the orientation of residue R490 played a key role in ligand binding. These findings reveal a unique mechanism of SORLA dimerization for protein trafficking.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Anjie Xia, Xihao Yong, Changbin Zhang, Guifeng Lin, Guowen Jia, Chang Zhao, Xin Wang, Yize Hao, Yifei Wang, Pei Zhou, Xin Yang, Yue Deng, Chao Wu, Yujiao Chen, Jiawei Zhu, Xiaodi Tang, Jingming Liu, Shiyu Zhang, Jiahao Zhang, Zheng Xu, Qian Hu, Jinlong Zhao, Yuting Yue, Wei Yan, Zhaoming Su, Yuquan Wei, Rongbin Zhou, Haohao Dong, Zhenhua Shao, Shengyong Yang
Summary: This study presents the cryo-EM structures of GPR34 bound with LysoPS and its inhibition by the antagonist YL-365. The findings provide mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, highlighting GPR34 as a promising target for disease treatment.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biology
Sang Soo Lee, Jun Gyou Park, Eunhong Jang, Seung Hun Choi, Subin Kim, Ji Won Kim, Mi Sun Jin
Summary: The W546A mutation in Human ATP-binding cassette transporter subfamily B6 (ABCB6) alters the conformational dynamics, resulting in reduced substrate affinity and facilitating its release from the transporter.
COMMUNICATIONS BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Kellie A. Woll, Omid Haji-Ghassemi, Filip Van Petegem
Summary: Ryanodine Receptors (RyRs) release Ca2+ and mutations in RyR can lead to various diseases such as malignant hyperthermia, myopathies, and arrhythmias. By investigating an MH-related RyR mutation and how apoCaM induces RyR1 opening, it is shown that disease mutations can cause distinct pathological conformations of RyR, affecting channel opening.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Le Thi My Le, James Robert Thompson, Sepehr Dehghani-Ghahnaviyeh, Shashank Pant, Phuoc Xuan Dang, Jarrod Bradley French, Takahisa Kanikeyo, Emad Tajkhorshid, Amer Alam
Summary: Phospholipid extrusion by ABC subfamily A (ABCA) exporters is essential for cellular physiology, but the molecular details of substrate interactions and transport mechanisms are still not well understood. In this study, cryo-EM structures of lipid-embedded human ABCA7 in different states were determined, revealing the structural framework for substrate entry and exit from ABCA7 and providing insights into the underlying conformational transitions. Combining functional analysis and molecular dynamics simulations, the study also shed light on lipid partitioning and localized membrane perturbations that contribute to ABCA7 function and may have implications for other ABCA family transporters.
Article
Multidisciplinary Sciences
Omar De Bei, Marialaura Marchetti, Luca Ronda, Eleonora Gianquinto, Loretta Lazzarato, Dimitri Y. Chirgadze, Steven W. Hardwick, Lee R. Cooper, Francesca Spyrakis, Ben F. Luisi, Barbara Campanini, Stefano Bettati
Summary: This study determines the structures of two IsdB:Hb complexes using single-particle cryo-electron microscopy, revealing the interaction mechanism between IsdB and Hb during heme extraction and the final step of heme transfer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Ying Li, Xizhen Ge
Summary: Multidrug resistance is a challenge to antibiotic therapy, mainly caused by efflux pumps in bacterial membranes. MFS efflux pumps are associated with quinolone resistance. This study used MdfA as a representative MFS efflux pump to investigate its conformational transition. Molecular dynamics simulations revealed an intermediate state between the inward and outward conformations, with protonation initiating the transition from outward to inward. Hydrophilic interaction and structural changes favored this process, while hydrophobic interaction and altered salt bridges facilitated substrate entrance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Vincent Chaptal, Veronica Zampieri, Benjamin Wiseman, Cedric Orelle, Juliette Martin, Kim-Anh Nguyen, Alexia Gobet, Margot Di Cesare, Sandrine Magnard, Waqas Javed, Jad Eid, Arnaud Kilburg, Marine Peuchmaur, Julien Marcoux, Luca Monticelli, Martin Hogbom, Guy Schoehn, Jean-Michel Jault, Ahcene Boumendjel, Pierre Falson
Summary: This study resolved three outward-facing conformations of BmrA, a multidrug ABC transporter, using x-ray crystallography and cryo-electron microscopy. It was found that two R6G molecules bind to the drug-binding cavity, inducing a rearrangement of TM1-2 and highlighting local flexibility. Simulations showed that in the absence of R6G, the cavity quickly closed after drug release, while in the presence of R6G, the cavity remained open.
Article
Biochemical Research Methods
Chih-Chia Su, Meinan Lyu, Christopher E. Morgan, Jani Reddy Bolla, Carol V. Robinson, Edward W. Yu
Summary: The development of the Build and Retrieve (BaR) method allows for the identification and determination of cryo-EM structures of various inner and outer membrane proteins from heterogeneous protein samples, demonstrating the potential of cryo-EM in systems structural proteomics.
Article
Biochemistry & Molecular Biology
Jianjun Fan, Yang Xiao, Matthias Quick, Yuwei Yang, Ziyi Sun, Jonathan A. Javitch, Xiaoming Zhou
Summary: The neurotransmitter:sodium symporter (NSS) homolog LeuT from Aquifex aeolicus is a valuable model for studying the transport mechanism of the NSS family. Crystal structures and studies on substrate binding dynamics suggest a potential competition between outward-open and outward-occluded states during substrate transport. The interplay between the protonation state of Glu290 and Na1 binding may regulate the outward-open-to-occluded transition.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Hidetaka Kohga, Takaharu Mori, Yoshiki Tanaka, Kunihito Yoshikaie, Katsuhide Taniguchi, Kei Fujimoto, Lisa Fritz, Tanja Schneider, Tomoya Tsukazaki
Summary: This study presents the crystal structures of inward-facing forms from Arsenophonus endosymbiont MurJ and an unprecedented squeezed form of Escherichia coli MurJ. Subsequent molecular dynamics simulations support the hypothesis that the squeezed form is an intermediate conformation.
Article
Multidisciplinary Sciences
Xiao Fan, Jian Huang, Xueqin Jin, Nieng Yan
Summary: Voltage-gated sodium channel Nav1.6 is crucial for neuronal firing and its dysfunction can lead to epilepsy and neurological disorders. The cryo-EM structure of human Nav1.6 reveals its inactivated state with closed pore domain and all up voltage-sensing domains. The presence of an unidentified molecule bound to the Nav1.6 PD suggests a potential target for developing specific blockers.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Clinical Neurology
Grace Hallinan, Kadir A. Ozcan, Md Rejaul Hoq, Laura Cracco, Frank S. Vago, Sakshibeedu R. Bharath, Daoyi Li, Max Jacobsen, Emma H. Doud, Amber L. Mosley, Anllely Fernandez, Holly J. Garringer, Wen Jiang, Bernardino Ghetti, Ruben Vidal
Summary: The aggregation of Prion protein (PrP) and formation of PrP amyloid (APrP) are crucial events in the development of prion diseases. Gerstmann-Straussler-Scheinker (GSS) disease, a dominantly inherited form of prion protein amyloidosis, is characterized by the presence of PrP amyloid plaques throughout the brain. Cryo-EM analysis of APrP filaments isolated from GSS patients with the F198S mutation revealed their complex structure, highlighting the importance of understanding filament structures in human neurodegenerative diseases.
ACTA NEUROPATHOLOGICA
(2022)
Article
Biochemistry & Molecular Biology
Dan-Dan Chen, Jia Hao, Chao-Hui Shen, Xian-Ming Deng, Cai-Hong Yun
Summary: The PA28 family proteasome activators play crucial roles in regulating proteasome activities. However, the paralogs, PA28 alpha, PA28 beta, and PA28 gamma, have distinct expression patterns, cellular localizations, and biological functions. This study provides an atomic resolution Cryo-EM structure of the human PA28 gamma heptamer, revealing unique structural features that may contribute to our understanding of its functional mechanisms.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Multidisciplinary Sciences
Jie Yin, Yanyong Kang, Aaron P. McGrath, Karen Chapman, Megan Sjodt, Eiji Kimura, Atsutoshi Okabe, Tatsuki Koike, Yuhei Miyanohana, Yuji Shimizu, Rameshu Rallabandi, Peng Lian, Xiaochen Bai, Mack Flinspach, Jef K. De Brabander, Daniel M. Rosenbaum
Summary: The OX2 orexin receptor (OX2R) is a highly expressed GPCR in the brain that regulates wakefulness and circadian rhythms. This study investigates how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a highly selective manner using cryo-electron microscopy.
NATURE COMMUNICATIONS
(2022)
Review
Chemistry, Multidisciplinary
Kai Cai, Xuewu Zhang, Xiao-chen Bai
Summary: Single-pass transmembrane receptors (SPTMRs) are a diverse group of membrane proteins involved in essential cellular processes. Understanding their mechanisms of action has been challenging due to the lack of full-length structures in different functional states. Recent developments in cryo-electron microscopy have led to significant progress in studying the structures of SPTMRs, improving our understanding of their function and mechanisms.
Review
Biochemistry & Molecular Biology
Eunhee Choi, Xiao-Chen Bai
Summary: The insulin receptor (IR) is a type II receptor tyrosine kinase that plays crucial roles in metabolism, growth, and proliferation. Recent advances in cryo-electron microscopy have allowed the determination of IR structures with different numbers of bound insulin molecules, providing important insights into the activation mechanism of this receptor. This review summarizes the insulin-induced activation mechanism of IR, including the binding modes and functions of insulin at different sites, as well as the structural transitions necessary for IR activation. It also highlights key aspects of IR signaling activation and regulation and suggests future research directions to fill the remaining gaps in our understanding.
ANNUAL REVIEW OF BIOCHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Guipeun Kang, Corey A. H. Allard, Wendy A. A. Valencia-Montoya, Lena van Giesen, Jeong Joo Kim, Peter B. B. Kilian, Xiaochen Bai, Nicholas W. W. Bellono, Ryan E. E. Hibbs
Summary: The study reveals that both octopus and squid have evolved cephalopod-specific chemotactile receptors (CRs) to sense their marine environments, with structural adaptations supporting the sensation of specific molecules suited to distinct physiological roles. Squid express ancient CRs more resembling nicotinic acetylcholine receptors, while octopuses exhibit a more recent expansion in CRs consistent with their elaborate 'taste by touch' sensory system. This study provides a foundation for understanding how adaptation of protein structure drives the diversification of organismal traits and behaviour.
Article
Biochemistry & Molecular Biology
Liwei Wang, Catherine Hall, Jie Li, Eunhee Choi, Xiao-chen Bai
Summary: The authors used cryo-EM to determine the structures of alkaline pH-induced insulin receptor-related receptor (IRR), revealing the mechanism of IRR activation by pH. Unlike other members of the insulin receptor family, IRR is activated by alkaline pH instead of ligand binding. Through mutagenesis and cellular assays, it was shown that the repulsion of pH-sensitive motifs disrupts the autoinhibited state of IRR and leads to a T-shaped active conformation. This study uncovers a novel pH-dependent activation mechanism of IRR, providing insights into its structure-function relationship.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Tian Xie, Guangjun Xu, Yun Liu, Bradley Quade, Weichun Lin, Xiao-chen Bai
Summary: MuSK is a receptor tyrosine kinase that is essential for the neuromuscular junction. Its activation requires both agrin and LRP4 coreceptors. This study presents the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK, revealing how LRP4 recruits agrin and MuSK to activate MuSK receptor.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Tian Xie, Peng Liu, Xinyue Wu, Feitong Dong, Zike Zhang, Jian Yue, Usha Mahawar, Faheem Farooq, Hisham Vohra, Qi Fang, Wenchen Liu, Binks W. Wattenberg, Xin Gong
Summary: The researchers elucidated the molecular mechanism of ceramide sensing by the SPT-ORMDL complex, which is tightly regulated by cellular sphingolipid levels. They found that the ORM/ORMDL family proteins can bind to specific sites of the serine palmitoyltransferase (SPT) complex after modifying cellular sphingolipids, leading to the inhibition of its activity. Furthermore, they discovered that mutations in the SPTLC1 subunit in childhood amyotrophic lateral sclerosis (ALS) patients impair ceramide sensing.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Peng Liu, Tian Xie, Xinyue Wu, Gongshe Han, Sita D. Gupta, Zike Zhang, Jian Yue, Feitong Dong, Kenneth Gable, Somashekarappa Niranjanakumari, Wanyuan Li, Lin Wang, Wenchen Liu, Ruifeng Yao, Edgar B. Cahoon, Teresa M. Dunn, Xin Gong
Summary: This study reveals the structure of the serine palmitoyltransferase (SPT) complex and its interaction with ORM/ORMDL proteins. ORM1 acts as a negative regulator of SPT by binding to a small molecule derived from steroid degradation, thereby controlling lipid synthesis and homeostasis. This has implications for plant responses to microbial attacks.
Article
Multidisciplinary Sciences
Shun Liu, Hua Chen, Yan Yin, Defen Lu, Guoming Gao, Jie Li, Xiao-Chen Bai, Xuewu Zhang
Summary: This study reveals that the nuclear protein BCCIP alpha binds to FAM46 and inhibits its PAP activity, thus affecting RNA stability. Structural analysis shows that BCCIP alpha, despite sharing most of the sequence with BCCIPII, adopts a unique fold completely different from BCCIPII. The unique fold of BCCIP alpha underlies its interaction with and functional regulation of FAM46.
Article
Biochemistry & Molecular Biology
Hongshan Zhang, Zhubing Shi, Edward J. Banigan, Yoori Kim, Hongtao Yu, Xiao-chen Bai, Ilya J. Finkelstein
Summary: This study provides direct evidence that CTCF binding polarity controls cohesin-mediated DNA looping and organization of the three-dimensional genome. It reveals that a specific motif of CTCF blocks cohesin translocation and DNA looping, and that CTCF polarity affects the compaction of DNA by cohesin. It also suggests that RNA-DNA hybrids may play a role in forming TAD boundaries and inhibiting DNA compaction by cohesin.
Article
Biochemistry & Molecular Biology
Jiyuan Zhang, Weizhong Zeng, Yan Han, Wan-Ru Lee, Jen Liou, Youxing Jiang
Summary: In this study, the researchers uncover the important role of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. They found that LAMP-1 and LAMP-2 interact with and inhibit the activity of the lysosomal cation channel TMEM175, leading to lysosomal acidification and optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction compromises lysosomal hydrolytic function. These findings have significant implications for lysosomal biology.
Review
Cell Biology
Xiao-chen Bai, Tamir Gonen, Angela M. Gronenborn, Anastassis Perrakis, Andrea Thorn, Jianyi Yang
Summary: Deciphering the intricate architecture of macromolecules is a formidable task, requiring a combination of empirical experimentation and artificial intelligence-based techniques. This Viewpoint discusses the key challenges and opportunities in this process.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jing Xue, Weizhong Zeng, Yan Han, Scott John, Michela Ottolia, Youxing Jiang
Summary: In this study, the cryo-EM structures of human cardiac NCX1 were presented, elucidating key structural elements for ion exchange and modulation by cytosolic Ca2+ and Na+.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Liwei Wang, Catherine E. Hall, Emiko Uchikawa, Dailu Chen, Eunhee Choi, Xuewu Zhang, Xiao-chen Bai
Summary: The researchers characterized insulin fibrils using cryo-EM and solved the structure of one fibril form. They designed several insulin mutants that can reduce fibrillation while maintaining the activity of insulin signaling, which may lead to more effective therapeutics for type 1 diabetes.
