Article
Biochemistry & Molecular Biology
Caitlin Walker, Yingjie Wang, Cristina Olivieri, V. S. Manu, Jiali Gao, David A. Bernlohr, Davide Calebiro, Susan S. Taylor, Gianluigi Veglia
Summary: Somatic mutations in the PRKACA gene lead to the development of Cushing's syndrome, with the E31V allosteric mutation disrupting communication nodes and nucleotide-substrate binding cooperativity. The loss of binding cooperativity in Cushing's syndrome mutants is proportional to the density of the intramolecular allosteric network, suggesting a common mechanism for this disease.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Chemistry, Medicinal
Christian Borgo, Luca Cesaro, Tsuyoshi Hirota, Keiko Kuwata, Claudio D'Amore, Thomas Ruppert, Renata Blatnik, Mauro Salvi, Lorenzo A. Pinna
Summary: CK2, a protein kinase with pleiotropic functions, is implicated in global human pathologies, particularly cancer. Selective inhibitors like CX4945 and GO289 show promise in controlling the CK2-dependent phosphoproteome.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Declan R. Creamer, Simon J. Hubbard, Mark P. Ashe, Chris M. Grant
Summary: Eukaryotic cells have developed a complex circuitry of signalling molecules to monitor changes in their environments. The cAMP/PKA pathway is an important glucose sensing circuit in yeast, and PKA activity regulates various processes in yeast growth. However, the molecular basis of PKA signalling specificity is poorly understood.
Article
Biochemistry & Molecular Biology
Christian Werner, Alexander Gast, Dirk Lindenblatt, Anna Nickelsen, Karsten Niefind, Joachim Jose, Jennifer Hochscherf
Summary: Specific mutations in the CSNK2A1 gene cause the OCNDS disease, which is a rare congenital disorder with diverse symptoms. A common mutation in the CK2 alpha protein leads to a shift in substrate specificity. Although the mutation does not affect protein stability or interaction with CK2 beta, it causes a significant change in the anion binding site.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Nehad Noby, Rachel L. Johnson, Jonathan D. Tyzack, Amira M. Embaby, Hesham Saeed, Ahmed Hussein, Sherine N. Khattab, Pierre J. Rizkallah, D. Dafydd Jones
Summary: The study on cold active esterase EstN7 reveals that its substrate range is limited but can be broadened through mutations, providing new insights for enzyme engineering.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Endocrinology & Metabolism
Daniela Dadej, Ewelina Szczepanek-Parulska, Elzbieta Wrotkowska, Marek Ruchala
Summary: Adipokines, such as fetuin A, fatty acid binding protein 4 (FABP4), and retinol binding protein 4 (RBP4), show altered concentrations in Cushing's syndrome, suggesting their potential involvement in metabolic dysregulation. Further research is needed to determine their precise role and significance in the development of metabolic complications associated with this syndrome.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Endocrinology & Metabolism
Renata Swiatkowska-Stodulska, Agata Berlinska, Katarzyna Stefanska, Przemyslaw Klosowski, Krzysztof Sworczak
Summary: Cyclic Cushing's syndrome is a disease characterized by periods of transient hypercortisolemia shifting into periods of normo- and/or hypocortisolemia. Diagnosis is based on at least three periods of confirmed hypercortisolemia interspersed by two periods of normocortisolemia. Due to its diverse clinical picture, unpredictable duration and frequency of phases, and various etiologies, cyclic Cushing's syndrome is a challenge in modern endocrinology.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Hieu Nguyen, Arminja N. Kettenbach
Summary: Dynamic protein phosphorylation and dephosphorylation play critical roles in cellular signaling and biological functions. Dysregulation of these processes has been linked to various human diseases. This review focuses on the mechanisms controlling the specific dephosphorylation of proteins. The majority of serine/threonine dephosphorylation is catalyzed by highly conserved phosphoprotein phosphatase (PPP) catalytic subunits, which form holoenzymes with regulatory and scaffolding subunits. PPP holoenzymes recognize phosphorylation site consensus motifs and interact with short linear motifs (SLiMs) or structural elements distal to the phosphorylation site. Recent advances in understanding the mechanisms of PPP site-specific dephosphorylation preference and substrate recruitment are discussed, with emphasis on their roles in regulating cell division.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Yao Chen, Bernardo L. Sabatini
Summary: In addition to inhibiting PKA activity, PKI was found to facilitate the activation of multiple isoforms of PKC at higher concentrations. This suggests the need for appropriate interpretation of experimental results when using PKI as a pharmaceutical agent. The study provides a foundation for exploring the potential functions of PKI in regulating PKC activity and coordinating PKC and PKA activities.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ludovica Lospinoso Severini, Elena Loricchio, Shirin Navacci, Irene Basili, Romina Alfonsi, Flavia Bernardi, Marta Moretti, Marilisa Conenna, Antonino Cucinotta, Sonia Coni, Marialaura Petroni, Enrico De Smaele, Giuseppe Giannini, Marella Maroder, Gianluca Canettieri, Angela Mastronuzzi, Daniele Guardavaccaro, Olivier Ayrault, Paola Infante, Francesca Bufalieri, Lucia Di Marcotullio
Summary: The Sonic Hedgehog (SHH) pathway plays a crucial role in embryonic development and stemness. The high expression of SALL4, a stemness regulator, is correlated with worse overall survival in patients with SHH-MB. SALL4 interacts with CRL3(REN) and enhances GLI1 transcriptional activity through cooperation with HDAC1. Inhibition of SALL4 suppresses the growth of SHH-MB in mouse models and patient-derived xenograft models, making it a promising therapeutic target.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Pharmacology & Pharmacy
Yi-Zheng Fang, Li Jiang, Qiaojun He, Ji Cao, Bo Yang
Summary: Deubiquitinating enzymes (DUBs) are crucial for regulating protein levels by facilitating the escape of proteins from ubiquitin-proteasome degradation. Although extensive research has been conducted on the ubiquitin chain specificity of DUBs, the mechanism of substrate protein recognition is still not well understood. In this study, we investigated the role of scaffolding proteins and complexes in DUB substrate selectivity and proposed a potential mechanism called deubiquitination complex platform (DCP) based on known examples, which may improve our understanding of DUB substrate specificity.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Biochemistry & Molecular Biology
Ilona Faustova, Kaidi Moll, Ervin Valk, Mart Loog, Mihkel Ord
Summary: Cyclins not only activate CDK complexes, but also serve as docking scaffolds for CDK substrates and inhibitors. G1-cyclins in yeast play a specific role in promoting bud growth and polarization, essential for cell survival. The discovery of a specific docking motif in G1-cyclins expands our understanding of cyclin specificity mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Silvia Martini, Khalil Davis, Rupert Faraway, Lisa Elze, Nicola Lockwood, Andrew Jones, Xiao Xie, Neil Q. McDonald, David J. Mann, Alan Armstrong, Jernej Ule, Peter J. Parker
Summary: PKC epsilon regulates the mitotic events by controlling translation and promoting the assembly of ribonucleoprotein granules containing SERBP1, which is essential for chromosome segregation and successful cell division independent of Aurora B. The authors demonstrate that SERBP1 acts as a parallel mitotic PKC epsilon substrate ensuring the integrity of chromosome segregation and successful cell division.
NATURE COMMUNICATIONS
(2021)
Letter
Chemistry, Physical
Dan Su, Tatsiana Kosciuk, Hening Lin
Summary: This article concludes that binding affinity is crucial for in vivo substrate specificity and proposes a method to identify substrate proteins for enzymes by utilizing existing interactome data. The Reply aims to clarify important points in the original article.
Article
Biochemistry & Molecular Biology
Elena Ostertag, Liujuan Zheng, Karina Broger, Thilo Stehle, Shu-Ming Li, Georg Zocher
Summary: Prenylation plays a crucial role in primary and secondary metabolism, contributing to chemical diversity in natural systems. Recent structural studies on prenyltransferases shed light on their catalytic mechanisms and key residues, but the control of regioselectivity and chemoselectivity remains a challenge. Site-directed mutagenesis has been successfully utilized to modify prenyl donor specificity and switch the regioselectivity of prenyltransferases, showing potential for production of novel prenylated compounds.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Oncology
Haisheng Zhang, Antje Schaefer, Yichen Wang, Richard G. Hodge, Devon R. Blake, J. Nathaniel Diehl, Alex G. Papageorge, Matthew D. Stachler, Jennifer Liao, Jin Zhou, Zhong Wu, Fahire G. Akarca, Leonie K. de Klerk, Sarah Derks, Mariaelena Pierobon, Katherine A. Hoadley, Timothy C. Wang, George Church, Kwok-Kin Wong, Emanuel F. Petricoin, Adrienne D. Cox, Douglas R. Lowy, Channing J. Der, Adam J. Bass
Article
Biochemical Research Methods
Shilpa Garg, John Aach, Heng Li, Isaac Sebenius, Richard Durbin, George Church
Article
Biochemistry & Molecular Biology
Jonathan M. Stokes, Kevin Yang, Kyle Swanson, Wengong Jin, Andres Cubillos-Ruiz, Nina M. Donghia, Craig R. MacNair, Shawn French, Lindsey A. Carfrae, Zohar Bloom-Ackerman, Victoria M. Tran, Anush Chiappino-Pepe, Ahmed H. Badran, Ian W. Andrews, Emma J. Chory, George M. Church, Eric D. Brown, Tommi S. Jaakkola, Regina Barzilay, James J. Collins
Review
Pharmacology & Pharmacy
Dong Niu, Xiang Ma, Taoyan Yuan, Yifan Niu, Yibin Xu, Zhongxin Sun, Yuan Ping, Weifen Li, Jufang Zhang, Tao Wang, George M. Church
Summary: Xenotransplantation of pig organs offers a potential solution to the shortage of donor organs for human patients but faces challenges such as immune rejection and the risk of porcine endogenous retrovirus transmission. Advances in genome engineering and immunosuppressive medications have the potential to overcome these barriers, leading to promising preclinical results and upcoming clinical trials for organs like islet, kidney, and heart transplantation.
ADVANCED DRUG DELIVERY REVIEWS
(2021)
Article
Multidisciplinary Sciences
Jessica A. Weber, Seung Gu Park, Victor Luria, Sungwon Jeon, Hak-Min Kim, Yeonsu Jeon, Youngjune Bhak, Je Hun Jun, Sang Wha Kim, Won Hee Hong, Semin Lee, Yun Sung Cho, Amir Karger, John W. Cain, Andrea Manica, Soonok Kim, Jae-Hoon Kim, Jeremy S. Edwards, Jong Bhak, George M. Church
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Editorial Material
Geriatrics & Gerontology
Brian P. Hanley, Steve Keen, George Church
REJUVENATION RESEARCH
(2020)
Article
Multidisciplinary Sciences
Kai Wang, Ruei-Zeng Lin, Xuechong Hong, Alex H. Ng, Chin Nien Lee, Joseph Neumeyer, Gang Wang, Xi Wang, Minglin Ma, William T. Pu, George M. Church, Juan M. Melero-Martin
Letter
Biotechnology & Applied Microbiology
Matthew J. MacKay, Anna C. Hooker, Ebrahim Afshinnekoo, Marc Salit, Jason Kelly, Jonathan V. Feldstein, Nick Haft, Doug Schenkel, Subhalaxmi Nambi, Yizhi Cai, Feng Zhang, George Church, Junbiao Dai, Cliff L. Wang, Shawn Levy, Jeff Huber, Hanlee P. Ji, Alison Kriegel, Anne L. Wyllie, Christopher E. Mason
NATURE BIOTECHNOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Jorge A. Marchand, Merrick D. Pierson Smela, Thomas H. H. Jordan, Kamesh Narasimhan, George M. Church
Summary: T-box riboswitches are a large family of tRNA-binding leader sequences that are crucial for gene regulation in many gram-positive bacteria. TBDB is an open-access database that contains a vast collection of T-box riboswitch sequences and provides structural annotations for this important family of regulatory RNA.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Engineering, Biomedical
Yanan Yue, Weihong Xu, Yinan Kan, Hong-Ye Zhao, Yixuan Zhou, Xiaobin Song, Jiajia Wu, Juan Xiong, Dharmendra Goswami, Meng Yang, Lydia Lamriben, Mengyuan Xu, Qi Zhang, Yu Luo, Jianxiong Guo, Shengyi Mao, Deling Jiao, Tien Dat Nguyen, Zhuo Li, Jacob V. Layer, Mailin Li, Violette Paragas, Michele E. Youd, Zhongquan Sun, Yuan Ding, Weilin Wang, Hongwei Dou, Lingling Song, Xueqiong Wang, Lei Le, Xin Fang, Haydy George, Ranjith Anand, Shi Yun Wang, William F. Westlin, Marc Guell, James Markmann, Wenning Qin, Yangbin Gao, Hong-Jiang Wei, George M. Church, Luhan Yang
Summary: Genetic engineering of pigs using a combination of CRISPR-Cas9 and transposon technologies allows for inactivation of endogenous retroviruses and enhancement of compatibility with the human immune system, providing a potential pathway for safe and effective porcine xenotransplantation.
NATURE BIOMEDICAL ENGINEERING
(2021)
Article
Chemistry, Multidisciplinary
Mirko Palla, Sukanya Punthambaker, Benjamin Stranges, Frederic Vigneault, Jeff Nivala, Daniel Wiegand, Aruna Ayer, Timothy Craig, Dmitriy Gremyachinskiy, Helen Franklin, Shaw Sun, James Pollard, Andrew Trans, Cleoma Arnold, Charles Schwab, Colin Mcgaw, Preethi Sarvabhowman, Dhruti Dalal, Eileen Thai, Evan Amato, Ilya Lederman, Meng Taing, Sara Kelley, Adam Qwan, Carl W. Fuller, Stefan Roever, George M. Church
Summary: The use of single-molecule DNA sequencing platform allows for rapid screening of polymerase variants, enabling the identification of enzymes with different features. This approach is valuable for applications requiring polymerases with altered physical properties.
Article
Biotechnology & Applied Microbiology
Alex H. M. Ng, Parastoo Khoshakhlagh, Jesus Eduardo Rojo Arias, Giovanni Pasquini, Kai Wang, Anka Swiersy, Seth L. Shipman, Evan Appleton, Kiavash Kiaee, Richie E. Kohman, Andyna Vernet, Matthew Dysart, Kathleen Leeper, Wren Saylor, Jeremy Y. Huang, Amanda Graveline, Jussi Taipale, David E. Hill, Marc Vidal, Juan M. Melero-Martin, Volker Busskamp, George M. Church
Summary: Using a library of human transcription factor genes, this study identified and utilized new transcription factors to directly program human pluripotent stem cells into various cell types, offering a novel approach in the field of cell engineering.
NATURE BIOTECHNOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Shilpa Garg, Arkarachai Fungtammasan, Andrew Carroll, Mike Chou, Anthony Schmitt, Xiang Zhou, Stephen Mac, Paul Peluso, Emily Hatas, Jay Ghurye, Jared Maguire, Medhat Mahmoud, Haoyu Cheng, David Heller, Justin M. Zook, Tobias Moemke, Tobias Marschall, Fritz J. Sedlazeck, John Aach, Chen-Shan Chin, George M. Church, Heng Li
Summary: The DipAsm method utilizes long, accurate reads and long-range conformation data to generate chromosome-scale phased assembly for single individuals within a day, demonstrating superior performance in both contiguity and phasing completeness compared to other approaches. DipAsm is crucial for the discovery of structural variants and highly polymorphic and medically important regions, facilitating high-quality precision medicine and studies of individual haplotype variation and population diversity.
NATURE BIOTECHNOLOGY
(2021)
Letter
Multidisciplinary Sciences
Lindsey R. Robinson-McCarthy, Alexander J. Mijalis, Gabriel T. Filsinger, Helena de Puig, Nina M. Donghia, Thomas E. Schaus, Robert A. Rasmussen, Raphael Ferreira, Jeantine E. Lunshof, George Chao, Dmitry Ter-Ovanesyan, Oliver Dodd, Erkin Kuru, Adama M. Sesay, Joshua Rainbow, Andrew C. Pawlowski, Timothy M. Wannier, Peng Yin, James J. Collins, Donald E. Ingber, George M. Church, Jenny M. Tam
Article
Multidisciplinary Sciences
Andrew C. Payne, Zachary D. Chiang, Paul L. Reginato, Sarah M. Mangiameli, Evan M. Murray, Chun-Chen Yao, Styliani Markoulaki, Andrew S. Earl, Ajay S. Labade, Rudolf Jaenisch, George M. Church, Edward S. Boydenit, Jason D. Buenrostrot, Fei Chen
Summary: In situ genome sequencing (IGS) allows for sequencing and imaging of genomes within intact biological samples, providing spatial localization of genomic loci and revealing parent-specific changes in genome structure across embryonic stages, single-cell chromatin domains in zygotes, and epigenetic memory of global chromosome positioning within individual embryos. These results demonstrate the capability of IGS to directly connect sequence and structure across length scales from single base pairs to whole organisms.