scholarly journals Inverting family GH156 sialidases define an unusual catalytic motif for glycosidase action

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pedro Bule ◽  
Léa Chuzel ◽  
Elena Blagova ◽  
Liang Wu ◽  
Melissa A. Gray ◽  
...  
Keyword(s):  
Hot Spring ◽  
Sialic Acids ◽  
Cellular Biology ◽  
Active Centre ◽  
Cellular Recognition ◽  
Health And Disease ◽  
Brønsted Base ◽  
Catalytic Motif ◽  
Technological Platforms ◽  
Inverting Mechanism

Abstract Sialic acids are a family of related sugars that play essential roles in many biological events intimately linked to cellular recognition in both health and disease. Sialidases are therefore orchestrators of cellular biology and important therapeutic targets for viral infection. Here, we sought to define if uncharacterized sialidases would provide distinct paradigms in sialic acid biochemistry. We show that a recently discovered sialidase family, whose first member EnvSia156 was isolated from hot spring metagenomes, defines an unusual structural fold and active centre constellation, not previously described in sialidases. Consistent with an inverting mechanism, EnvSia156 reveals a His/Asp active center in which the His acts as a Brønsted acid and Asp as a Brønsted base in a single-displacement mechanism. A predominantly hydrophobic aglycone site facilitates accommodation of a variety of 2-linked sialosides; a versatility that offers the potential for glycan hydrolysis across a range of biological and technological platforms.

scholarly journals A modular tool to query and inducibly disrupt biomolecular condensates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carmen N. Hernández-Candia ◽  
Sarah Pearce ◽  
Chandra L. Tucker
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cellular Function ◽  
Biological Role ◽  
Cellular Biology ◽  
Condensate Formation ◽  
Health And Disease ◽  
Lateral Sclerosis

AbstractDynamic membraneless compartments formed by protein condensates have multifunctional roles in cellular biology. Tools that inducibly trigger condensate formation have been useful for exploring their cellular function, however, there are few tools that provide inducible control over condensate disruption. To address this need we developed DisCo (Disassembly of Condensates), which relies on the use of chemical dimerizers to inducibly recruit a ligand to the condensate-forming protein, triggering condensate dissociation. We demonstrate use of DisCo to disrupt condensates of FUS, associated with amyotrophic lateral sclerosis, and to prevent formation of polyglutamine-containing huntingtin condensates, associated with Huntington’s disease. In addition, we combined DisCo with a tool to induce condensates with light, CRY2olig, achieving bidirectional control of condensate formation and disassembly using orthogonal inputs of light and rapamycin. Our results demonstrate a method to manipulate condensate states that will have broad utility, enabling better understanding of the biological role of condensates in health and disease.

Fifty-eight years in science – a commentary

2005 ◽  
Vol 83 (8-9) ◽  
pp. 657-663 ◽  
Author(s):  
Edwin E Daniel
Keyword(s):  
Smooth Muscle ◽  
World War Ii ◽  
Problem Based Learning ◽  
Cellular Biology ◽  
World War ◽  
University Of Alberta ◽  
Muscle Research ◽  
Helping Others ◽  
Health And Disease ◽  
The University

After 58 years in science, mostly in pharmacology, one gains perspective. Mine is that there have been important changes over this time, some good and some questionable. In this commentary, I try to reveal how I got to this stage, partially explaining my biases, and possibly helping others learn from my experiences including mistakes. Changing from seeking an M.D. to cellular biology and then to pharmacology early in my career were the best moves I made. The next best move was migration to Canada, away from the McCarthy-McCarran hysteria. Arriving at a time after the end of World War II when science in Canada was expanding was very good luck. I had an excellent opportunity to enjoy both the administration (as Chair of the first independent Department of Pharmacology at the University of Alberta) and the practice of pharmacology (as a practitioner of research on smooth muscle in health and disease). For me, the practice of research has always won over administration when a choice had to be made. Early on, I began to ask questions about educational practices and tried to evaluate them. This led me to initiate changes in laboratories and to seek nondidactic educational approaches such as problem-based learning. I also developed questions about the practice of anonymous peer review. After moving to McMaster in 1975, I was compelled to find a solution for a failed "Pharmacology Program" and eventually developed the first "Smooth Muscle Research Program". Although that was a good solution for the research component, it did not solve the educational needs. This led to the development of "therapeutic problems", which were used to help McMaster medical students educate themselves about applied pharmacology. Now these problems are being used to educate pharmacology honours and graduate students at the University of Alberta. The best part of all these activities is the colleagues and friends that I have interacted with and learned from over the years, and the realization that many of them have collaborated with me again in this volume.Key words: bias and anonymity, problem-based learning, research versus administration, smooth muscle.

scholarly journals Limited Hydrolysis of Polysialic Acid by Human Neuraminidase Enzymes

2021 ◽  
Author(s):  
Carmanah D. Hunter ◽  
Christopher Cairo
Keyword(s):  
Polysialic Acid ◽  
Chemical Properties ◽  
Sialic Acids ◽  
Degree Of Polymerization ◽  
Health And Disease ◽  
Substrate Tolerance ◽  
The Impact ◽  
Hydrolysis Of ◽  
Unique Chemical

Regulation of sialic acids by human neuraminidase (hNEU) enzymes is important to many biological processes. Defining hNEU substrate tolerance can help to elucidate the roles of these enzymes in regulating sialosides in human health and disease. Polysialic acid (polySia) is a polyanion of α(2→8) linked sialic acids with roles in nervous, reproductive, and immune systems and is dysregulated in some malignancies and mental disorders. The unique chemical properties of this polymer, which include an enhanced susceptibility to acid-catalyzed hydrolysis, have hampered its study. Herein we describe the first<i> </i>systematic study of hNEU isoenzyme activity towards polysialic acid <i>in vitro.</i> The experimental design allowed us to study the impact of several factors that may influence polysialic acid degradation including pH, polymer size, and the relative ionic strength of the surrounding media. We report that short chains of polysialic acid (degree of polymerization, DP 3-8) were substrates of NEU3 and NEU4 at acidic pH, but not at neutral pH. No hNEU-catalyzed hydrolysis of longer polymers (DP 10-20) was detected. These findings suggest a neuraminidase-independent mechanism for polysialic acid turnover such as internalization and degradation in endosomes and lysosomes.

Report on the Bicarbonate Transport Satellite Meeting at the 53rd Annual Meeting of the Canadian Society of Biochemistry, Molecular and Cellular Biology

2011 ◽  
Vol 89 (2) ◽  
pp. 83-84
Author(s):  
Reinhart A.F. Reithmeier ◽  
Joseph R. Casey
Keyword(s):  
Annual Meeting ◽  
Cellular Biology ◽  
Bicarbonate Transport ◽  
Canadian Society ◽  
Electron Crystallography ◽  
Bicarbonate Transporter ◽  
Bicarbonate Transporters ◽  
History Of ◽  
Health And Disease

The Bicarbonate Transport Meeting was held as a satellite meeting of the 53rd Annual Meeting of the Canadian Society of Biochemistry, Molecular and Cellular Biology (CSBMCB): Membrane Proteins in Health and Disease. The meeting covered the modern history of bicarbonate transporter proteins and brought together the major workers in the field. Ron Kopito recounted the story of the first determination of the amino acid sequence for a bicarbonate transporter, AE1/Band 3, 25 years earlier while working with Harvey Lodish at Harvard, while Tomohiro Yamaguchi and Teruhisa Hirai presented up-to-date data on AE1 structure obtained using electron crystallography. The meeting further spanned the spectrum of bicarbonate transporters, with sessions devoted to Cl–/HCO3– exchangers, Na+/HCO3– co-transporters, the link to carbonic anhydrase, and the SLC26 family of bicarbonate transporters expressed broadly in humans, yeast, and bacteria.

scholarly journals Advances in spatial transcriptomic data analysis

2021 ◽  
Vol 31 (10) ◽  
pp. 1706-1718 ◽  
Author(s):  
Ruben Dries ◽  
Jiaji Chen ◽  
Natalie del Rossi ◽  
Mohammed Muzamil Khan ◽  
Adriana Sistig ◽  
...  
Keyword(s):  
Data Analysis ◽  
Spatial Organization ◽  
Transcriptomic Data ◽  
Tissue Organization ◽  
Gene Coverage ◽  
Health And Disease ◽  
Solid Foundation ◽  
Downstream Analysis ◽  
Subcellular Resolution ◽  
Technological Platforms

Spatial transcriptomics is a rapidly growing field that promises to comprehensively characterize tissue organization and architecture at the single-cell or subcellular resolution. Such information provides a solid foundation for mechanistic understanding of many biological processes in both health and disease that cannot be obtained by using traditional technologies. The development of computational methods plays important roles in extracting biological signals from raw data. Various approaches have been developed to overcome technology-specific limitations such as spatial resolution, gene coverage, sensitivity, and technical biases. Downstream analysis tools formulate spatial organization and cell–cell communications as quantifiable properties, and provide algorithms to derive such properties. Integrative pipelines further assemble multiple tools in one package, allowing biologists to conveniently analyze data from beginning to end. In this review, we summarize the state of the art of spatial transcriptomic data analysis methods and pipelines, and discuss how they operate on different technological platforms.

scholarly journals Limited Hydrolysis of Polysialic Acid by Human Neuraminidase Enzymes

2021 ◽  
Author(s):  
Carmanah D. Hunter ◽  
Christopher Cairo
Keyword(s):  
Polysialic Acid ◽  
Chemical Properties ◽  
Sialic Acids ◽  
Degree Of Polymerization ◽  
Health And Disease ◽  
Substrate Tolerance ◽  
The Impact ◽  
Hydrolysis Of ◽  
Unique Chemical

Regulation of sialic acids by human neuraminidase (hNEU) enzymes is important to many biological processes. Defining hNEU substrate tolerance can help to elucidate the roles of these enzymes in regulating sialosides in human health and disease. Polysialic acid (polySia) is a polyanion of α(2→8) linked sialic acids with roles in nervous, reproductive, and immune systems and is dysregulated in some malignancies and mental disorders. The unique chemical properties of this polymer, which include an enhanced susceptibility to acid-catalyzed hydrolysis, have hampered its study. Herein we describe the first<i> </i>systematic study of hNEU isoenzyme activity towards polysialic acid <i>in vitro.</i> The experimental design allowed us to study the impact of several factors that may influence polysialic acid degradation including pH, polymer size, and the relative ionic strength of the surrounding media. We report that short chains of polysialic acid (degree of polymerization, DP 3-8) were substrates of NEU3 and NEU4 at acidic pH, but not at neutral pH. No hNEU-catalyzed hydrolysis of longer polymers (DP 10-20) was detected. These findings suggest a neuraminidase-independent mechanism for polysialic acid turnover such as internalization and degradation in endosomes and lysosomes.

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