Review
Biochemistry & Molecular Biology
Nina Horn, Pernilla Wittung-Stafshede
Summary: Copper is essential for cellular functions, with ATP7A playing a critical role in copper balance. Dysfunction of ATP7A leads to Menkes disease, characterized by copper deficiency and accumulation in different tissues. Studying the roles of copper enzymes in Menkes disease can provide insights into disease mechanisms and improve early diagnosis accuracy.
Review
Cell Biology
Som Dev, Robert L. Kruse, James P. Hamilton, Svetlana Lutsenko
Summary: This review summarizes recent advances in the characterization of Wilson disease pathophysiology and discusses emerging targets for improving diagnosis and treatment.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Gastroenterology & Hepatology
Christopher J. Collins, Fan Yi, Remwilyn Dayuha, Phi Duong, Simon Horslen, Michelle Camarata, Ayse K. Coskun, Roderick H. J. Houwen, Tudor L. Pop, Heinz Zoller, Han-Wook Yoo, Sung Won Jung, Karl H. Weiss, Michael L. Schilsky, Peter Ferenci, Si Houn Hahn
Summary: Quantification of ATP7B peptide effectively identified Wilson disease patients in 92.1% of presented cases, reducing ambiguities from ceruloplasmin and genetic analysis. It provides clarity to patients with ambiguous genetic results, aiding significantly in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be a rapid supplement to current Leipzig scoring systems.
Review
Biochemistry & Molecular Biology
Bryce Blades, Scott Ayton, Ya Hui Hung, Ashley Bush, Sharon La Fontaine
Summary: The complex and inverse relationship between copper and lipid metabolism has implications for diseases involving dyslipidemia. Understanding these pathways may provide druggable targets for therapeutic intervention. Tissue-specific roles of the copper regulatory protein ATP7B further elucidate the association between copper and lipid metabolism.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2021)
Review
Medicine, General & Internal
Ana Lucena-Valera, Pilar Ruz-Zafra, Javier Ampuero
Summary: Wilson's disease is a rare hereditary disorder caused by a deficiency in the ATP7B transporter. It results in copper accumulation primarily in the liver, and secondarily in other organs such as the central nervous system. The disease has a wide spectrum of symptoms, ranging from asymptomatic to acute liver failure. Diagnosis requires a combination of clinical signs, symptoms, and diagnostic tests. Treatment involves lifelong maintenance with chelating agents and copper absorption inhibitors, and liver transplant may be an option for end-stage liver disease patients.
Review
Endocrinology & Metabolism
S. De Feyter, A. Beyens, B. Callewaert
Summary: Counseling in ATP7A-related disorders is challenging due to clinical overlap, lack of predictive biomarkers, and genotype-phenotype correlation. A systematic literature review identified clinical criteria, evaluated genotype-phenotype correlations, and proposed management guidelines based on data from 162 individuals with confirmed ATP7A-related disorders.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Article
Genetics & Heredity
Guo-Min Yang, Rou-Min Wang, Nan Xia, Zi-Wei Zheng, Yi Dong, Zhi-Ying Wu
Summary: This study revealed a regional-specific distribution feature for p.T935M in mainland Chinese population. Linkage disequilibrium was shown at the three markers for all three variants, with common haplotypes specific for p.R778L, p.P992L, and p.T935M identified. These common haplotypes indicate a founder effect contributing to the emergence of the three prevalent pathogenic variants observed in Wilson's disease, expanding our understanding of genetic diversity across regions.
Review
Biochemistry & Molecular Biology
Ana Sanchez-Monteagudo, Edna Ripolles, Marina Berenguer, Carmen Espinos
Summary: Wilson disease is a rare disorder with a variable clinical presentation, requiring early diagnosis for effective treatment. The clinical diagnosis is based on the Leipzig score, but some patients may have conditions resembling WD, leading to uncertainty. Current biomarkers like ceruloplasmin and copper levels are not sufficient, highlighting the need for better markers to improve diagnosis and prognosis.
Article
Multidisciplinary Sciences
Dipankar Ash, Varadarajan Sudhahar, Seock-Won Youn, Mustafa Nazir Okur, Archita Das, John P. O'Bryan, Maggie McMenamin, Yali Hou, Jack H. Kaplan, Tohru Fukai, Masuko Ushio-Fukai
Summary: This study reveals a previously unknown interaction between the Copper transporter ATP7A, autophagy, and VEGFR2 degradation in endothelial cells, highlighting the importance of ATP7A in regulating VEGFR2 signaling and angiogenesis. The findings suggest that ATP7A acts as a potential therapeutic target for ischemic cardiovascular diseases by promoting VEGFR2-mediated angiogenesis and neovascularization.
NATURE COMMUNICATIONS
(2021)
Article
Medical Laboratory Technology
Siyu Jia, Xiaojin Li, Wei Zhang, Bei Zhang, Zhen Wu, Weijia Duan, Xiaojuan Ou, Donghu Zhou, Jian Huang
Summary: In this study, a reliable microarray system was established for the rapid detection of 24 ATP7B mutations in Chinese patients with Wilson disease. The microarray showed high sensitivity and specificity, making it a suitable method for genetic diagnosis of Wilson disease in China.
JOURNAL OF CLINICAL LABORATORY ANALYSIS
(2022)
Article
Pediatrics
Aabha Nagral, Snehal Mallakmir, Nikita Garg, Kritika Tiwari, Suzena Masih, Nishtha Nagral, Ojas Unavane, Ajay Jhaveri, Shubha Phadke, GaneshPrasad ArunKumar, Rakesh Aggarwal
Summary: This study reports genotype data of Wilson disease patients from India, adding to the available spectrum of causative variants in ATP7B gene. It also found genetic and phenotypic diversity in the Indian population.
INDIAN JOURNAL OF PEDIATRICS
(2023)
Article
Medical Laboratory Technology
Chenjun Huang, Meng Fang, Xiao Xiao, Zhiyuan Gao, Ying Wang, Chunfang Gao
Summary: This study revealed the genetic defects of Chinese families and individuals with Wilson disease, enriching the worldwide mutation spectrum of the ATP7B gene and providing valuable information for studying ATP7B mutation types in the Chinese population.
JOURNAL OF CLINICAL LABORATORY ANALYSIS
(2022)
Article
Gastroenterology & Hepatology
Mingming Li, Jing Ma, Wenlong Wang, Xu Yang, Kaizhong Luo
Summary: In this study, three novel mutations were identified in 103 WD patients from southern China, enriching the mutational spectrum of the ATP7B gene. The most common mutations were c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu), with allelic frequencies of 28.6% and 13.0%, respectively. Phenotype-genotype correlation analysis revealed significant associations between certain mutations and clinical characteristics of WD, providing insights into the population genetics of WD in China.
BMC GASTROENTEROLOGY
(2021)
Article
Neurosciences
Lisbeth Birk Moller, Mie Mogensen, David D. Weaver, Per Amstrup Pedersen
Summary: Disease-causing variants in ATP7A result in Menkes disease and occipital horn syndrome, with mutations leading to skipping of exon 10 or exon 15 not encoding functional protein variants. Higher amounts of wild-type ATP7A transcript are present in occipital horn syndrome compared with Menkes disease, indicating that even a small percentage of wild-type transcript can permit the occipital horn syndrome phenotype.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Cell Biology
Federico Catalano, Thomas J. O'Brien, Aleksandra A. Mekhova, Lucia Vittoria Sepe, Mariantonietta Elia, Rossella De Cegli, Ivan Gallotta, Pamela Santonicola, Giuseppina Zampi, Ekaterina Y. Ilyechova, Aleksei A. Romanov, Polina D. Samuseva, Josephine Salzano, Raffaella Petruzzelli, Elena V. Polishchuk, Alessia Indrieri, Byung-Eun Kim, Andre E. X. Brown, Ludmila V. Puchkova, Elia Di Schiavi, Roman S. Polishchuk
Summary: This study generated a mutant Caenorhabditis elegans strain to study copper toxicity in Wilson disease. The mutant animals exhibited poor resistance to copper and displayed developmental delay, shortened lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. The findings suggest that the mutant strain could be a valuable model for studying copper toxicity in Wilson disease.
Article
Neurosciences
William Kristian Karlsson, Joan Lilja Sunnleyg Hojgaard, Anna Vilhelmsen, Clarissa Crone, Birgit Andersen, Ian Law, Lisbeth Birk Moller, Troels Tolstrup Nielsen, Emilie Neerup Nielsen, Thomas Krag, Kirsten Svenstrup, Jorgen Erik Nielsen
Summary: Pathogenic variants in the SYNE1 gene can lead to a range of symptoms from pure ataxia to multisystemic disease. This case study presents a novel homozygous truncating variant in the SYNE1 gene in a 20-year-old female patient with early-onset cerebellar deficits, motor neuron involvement, and cognitive deficits, expanding the understanding of the phenotypic spectrum associated with SYNE1 mutations. The findings also reveal unique neuroimaging and electrophysiological abnormalities that further characterize the disease presentation.
Article
Biology
Thibaud Dieudonne, Sara Abad Herrera, Michelle Juknaviciute Laursen, Maylis Lejeune, Charlott Stock, Kahina Slimani, Christine Jaxel, Joseph A. Lyons, Cedric Montigny, Thomas Guenther Pomorski, Poul Nissen, Guillaume Lenoir
Summary: Research reveals that the human lipid flippase ATP8B1-CDC50A is autoinhibited by its N- and C-terminal tails, and ATP hydrolysis is unleashed by truncation of the C-terminus. However, it also requires phosphoinositides for full activation. Restoring inhibition of ATP8B1 truncation constructs with a synthetic peptide suggests molecular communication between the N- and C-termini and interference with the regulatory mechanism by exogenous compounds.
Article
Cell Biology
Liying Zhang, Kaituo Wang, Shuo Ning, Per Amstrup Pedersen, Annette Susanne Duelli, Pontus Emanuel Gourdon
Summary: In this study, the production and purification procedure of the D156C form of ChR2, which exhibits prolonged channel opening, was reported. Furthermore, conditions for growing ChR2 crystals that scatter X-rays to 6 angstrom were developed. The results provide a foundation for future structural studies of ChR2 in different states.
Article
Chemistry, Analytical
Kamil Gorecki, Jesper S. Hansen, Ping Li, Niloofar Nayeri, Karin Lindkvist-Petersson, Pontus Gourdon
Summary: In this study, a microfluidic-derived approach was demonstrated for visualizing and measuring membranous copper flux. The method involved the use of giant unilamellar vesicles reconstituted with the membrane protein of interest and a quencher-sensor reporter system for copper detection. This novel approach overcomes common issues encountered in studying heavy metal-ion flux and provides a new platform for in vitro studies of metal homeostasis.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Marlene U. Fruergaard, Ingrid Dach, Jacob L. Andersen, Mette Ozol, Azadeh Shahsavar, Esben M. Quistgaard, Hanne Poulsen, Natalya U. Fedosova, Poul Nissen
Summary: In this study, the crystal structure and functional properties of the E2-BeFx complex of pig kidney Na+,K+-ATPase are investigated. The complex resembles the E2P intermediate and is able to bind ADP/ATP and Na+. The results suggest a relation between E2-BeFx and the E*P intermediate in the functional cycle of Na+, K+-ATPase.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Ping Li, Amber L. Hendricks, Yong Wang, Rhiza Lyne E. Villones, Karin Lindkvist-Petersson, Gabriele Meloni, J. A. Cowan, Kaituo Wang, Pontus Gourdon
Summary: This study utilizes cryo-EM to reveal the structure of Atm1 transporter and proposes its molecular mechanism in the maturation of iron-sulfur proteins. These findings are of significant importance for understanding the transport mechanism of eukaryotic ABCB7-type proteins.
NATURE COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Caroline Neumann, Dorota Focht, Sofia Trampari, Joseph A. Lyons, Poul Nissen
Summary: The bacterial amino-acid transporter MhsT from the SLC6A family has been crystallized in complex with different substrates to investigate the determinants of substrate specificity. Surprisingly, crystals of the MhsT-substrate complexes formed interrelated but distinct crystal-packing arrangements, presenting challenges in space-group assignment and structure determination due to pseudosymmetry, twinning, and translational noncrystallographic symmetry.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Caroline Neumann, Lena Lindtoft Rosenbaek, Rasmus Kock Flygaard, Michael Habeck, Jesper Lykkegaard Karlsen, Yong Wang, Kresten Lindorff-Larsen, Hans Henrik Gad, Rune Hartmann, Joseph Anthony Lyons, Robert A. Fenton, Poul Nissen
Summary: The sodium-potassium-chloride transporter NKCC1 is a crucial protein involved in ion uptake across plasma membranes. This study presents the cryo-electron microscopy structure of human NKCC1 and provides insights into its functional mechanism. The findings have implications for understanding the structure-function relationship of NKCC1 and other related proteins.
Article
Multidisciplinary Sciences
Peng Huang, Raminta Venskutonyte, Rashmi B. B. Prasad, Hamidreza Ardalani, Sofia W. W. de Mare, Xiao Fan, Ping Li, Peter Spegel, Nieng Yan, Pontus Gourdon, Isabella Artner, Karin Lindkvist-Petersson
Summary: Researchers have determined the cryo-EM structure of AQP7, a glycerol channel, composed of two adhering tetramers with well-defined densities in the central pore. AQP7 plays a critical physiological role in facilitating glycerol flux across the plasma membrane, and its structure may have implications for understanding metabolism, obesity, and related diseases.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Carolin Hoefner, Tenna Holgersen Bryde, Celina Pihl, Sylvia Naiga Tiedemann, Sophie Emilie Bresson, Hajira Ahmed Hotiana, Muhammad Saad Khilji, Theodore Dos Santos, Michele Puglia, Paola Pisano, Mariola Majewska, Julia Durzynska, Kristian Klindt, Justyna Klusek, Marcelo J. Perone, Robert Bucki, Per Marten Hagglund, Pontus Emanuel Gourdon, Kamil Gotfryd, Edyta Urbaniak, Malgorzata Borowiak, Michael Wierer, Patrick Edward MacDonald, Thomas Mandrup-Poulsen, Michal Tomasz Marzec
Summary: Apart from known functions, such as chaperoning and disulfide bond formation, the complete molecular sequence of proinsulin folding remains unclear. In this study, we investigated the role of FKBP2, an ER-resident proline isomerase, in proinsulin folding. Through experiments and analysis, we found that FKBP2 depletion resulted in misfolding of proinsulin and increased apoptosis in pancreatic beta-cells. Additionally, we observed an overexpression of FKBP2 mRNA in beta-cells from pancreatic islets of type 2 diabetes patients. These findings suggest that FKBP2 plays a crucial role in the correct folding of proinsulin.
Article
Biochemistry & Molecular Biology
Samuel A. J. Trammell, Luke F. Gamon, Kamil Gotfryd, Katja Thoroe Michler, Bandar D. Alrehaili, Iben Rix, Filip K. Knop, Pontus Gourdon, Yoon-Kwang Lee, Michael J. Davies, Matthew P. Gillum, Trisha J. Grevengoed
Summary: The study demonstrates that NATs, bioactive lipids involved in glucose homeostasis and lipid metabolism, are synthesized in human and mouse livers. The hepatic NAT synthase activity depends on BAAT, which expands the known substrates of BAAT beyond classic bile acids. This finding enhances our understanding of lipid metabolism and the role of bioactive lipids.
JOURNAL OF LIPID RESEARCH
(2023)
Article
Biochemical Research Methods
Niloofar Nayeri, Ping Li, Kamil Gorecki, Karin Lindkvist-Petersson, Pontus Gourdon
Summary: Transition metals like copper and zinc are essential for most organisms but can also be toxic at elevated levels. The Copper TRansporter protein family (CTRs) is responsible for maintaining appropriate levels of copper and has potential applications in cancer drug delivery and antifungal therapies. However, the structure, function, and regulation of CTRs are still not well understood, limiting their use in applied sciences. In this study, we report procedures to isolate and characterize CTR members using Saccharomyces cerevisiae as a production host, providing valuable insights for further research and drug discovery efforts.
PROTEIN EXPRESSION AND PURIFICATION
(2023)
Article
Biochemical Research Methods
Tamim Al-Jubair, Jonas Hyld Steffen, Julie Winkel Missel, Philip Kitchen, Mootaz M. Salman, Roslyn M. Bill, Pontus Gourdon, Susanna Tornroth-Horsefield
Summary: This article describes a protocol for characterizing the interaction between a human AQP and a soluble interaction partner using microscale thermophoresis (MST). The protocol provides a high level of control over components and environment, allowing for investigation of AQP protein-protein interactions with low sample consumption and high detergent compatibility.
Article
Biochemical Research Methods
Tamim Al-Jubair, Jonas Hyld Steffen, Julie Winkel Missel, Philip Kitchen, Mootaz M. Salman, Roslyn M. Bill, Pontus Gourdon, Susanna Tornroth-Horsefield
Summary: This article presents a protocol for high-yield recombinant expression and purification of human AQPs in the methylotropic yeast Pichia pastoris.
Article
Biochemical Research Methods
Jonas Hyld Steffen, Julie Winkel Missel, Tamim Al-Jubair, Philip Kitchen, Mootaz M. Salman, Roslyn M. Bill, Susanna Tornroth-Horsefield, Pontus Gourdon
Summary: AQPs, as critical water channels, play an important role in maintaining water homeostasis. This protocol describes a method to determine the water permeation capacity of AQPs by tracking the change in proteoliposome size exposed to an osmogenic gradient.