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Different phenotypic outcome due to site-specific phosphorylation in the cancer-associated NQO1 enzyme studied by phosphomimetic mutations

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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2022年第0期729卷 000-000页

作者： Pacheco-Garcia, Juan Luis Anoz-Carbonell, Ernesto Loginov, Dmitry S. Vankova, Pavla Salido, Eduardo Man, Petr Medina, Milagros Palomino-Morales, Rogelio Pey, Angel L. Univ Granada Dept Quim Fis Ave Fuentenueva S-N Granada 18071 Spain Univ Zaragoza Fac Ciencias Dept Bioquim & Biol Mol & Cellular Inst Biocomp & Fis Sistemas Complejos BIFIGBsC CS Zaragoza 50009 Spain Acad Sci Czech Republ Inst Microbiol BioCeV Prumyslova 595 Vestec 25250 Czech Republic Acad Sci Czech Republ Inst Biotechnol BioCeV Prumyslova 595 Vestec 25250 Czech Republic Univ La Laguna Hosp Univ Canarias Ctr Rare Dis CIBERER Tenerife 38320 Spain Univ Granada Fac Sci Dept Biochem & Mol Biol 1 Granada Spain Univ Granada Biomed Res Ctr CIBM Granada Spain Univ Granada Dept Quim Fis Un Excelencia Quim Aplicada Biomed & Medioambiente Ave Fuentenueva S-N Granada 18071 Spain Univ Granada Inst Biotecnol Ave Fuentenueva S-N Granada 18071 Spain

Protein phosphorylation is a common phenomenon in human flavoproteins although the functional consequences of this site-specific modification are largely unknown. Here, we evaluated the effects of site-specific phosphorylation (using phosphomimetic mutations at sites S40, S82 and T128) on multiple functional aspects as well as in the structural stability of the antioxidant and disease-associated human flavoprotein NQO1 using biophysical and biochemical methods. In vitro biophysical studies revealed effects of phosphorylation at different sites such as decreased binding affinity for FAD and structural stability of its binding site (S82), conformational stability (S40 and S82) and reduced catalytic efficiency and functional cooperativity (T128). Local stability measurements by H/D exchange in different ligation states provided structural insight into these effects. Transfection of eukaryotic cells showed that phosphorylation at sites S40 and S82 may reduce steady-levels of NQO1 protein by enhanced proteasome-induced degradation. We show that site-specific phosphorylation of human NQO1 may cause pleiotropic and counterintuitive effects on this multifunctional protein with potential implications for its relationships with human disease. Our approach allows to establish relationships between site-specific phosphorylation, functional and structural stability effects in vitro and inside cells paving the way for more detailed analyses of phosphorylation at the flavoproteome scale.

关键词： Flavoprotein Phosphorylation structure-function relationships

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Cryo-EM structures of a lipid-sensitive pentameric ligand-gated ion channel embedded in a phosphatidylcholine-only bilayer

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020年第3期117卷 1788-1798页

作者： Kumar, Pramod Wang, Yuhang Zhang, Zhening Zhao, Zhiyu Cymes, Gisela D. Tajkhorshid, Emad Grosman, Claudio Univ Illinois Dept Mol & Integrat Physiol Urbana IL 61801 USA Univ Illinois Ctr Biophys & Quantitat Biol Urbana IL 61801 USA Univ Illinois Dept Biochem Urbana IL 61801 USA Beckman Inst Adv Sci & Technol NIH Ctr Macromol Modeling & Bioinformat Urbana IL 61801 USA New York Struct Biol Ctr Simons Electron Microscopy Ctr Natl Resource Automated Mol Microscopy New York NY 10027 USA Univ Illinois Neurosci Program Urbana IL 61801 USA

The lipid dependence of the nicotinic acetylcholine receptor from the Torpedo electric organ has long been recognized, and one of the most consistent experimental observations is that, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity. More recently, it has been suggested that the bacterial homolog ELIC (Erwinia chrysanthemi ligand-gated ion channel) has a similar lipid sensitivity. As a first step toward the elucidation of the structural basis of this phenomenon, we solved the structures of ELIC embedded in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-angstrom resolution) and agonist-bound (3.3 angstrom) states using single-particle cryoelectron microscopy. Comparison of the two structural models revealed that the largest differences occur at the level of loop C-at the agonist-binding sites-and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). On the other hand, the transmembrane pore is occluded in a remarkably similar manner in both structures. A straightforward interpretation of these findings is that POPC-only membranes frustrate the ECD-TMD coupling in such a way that the "conformational wave" of liganded-receptor gating takes place in the ECD and the interfacial M2-M3 linker but fails to penetrate the membrane and propagate into the TMD. Furthermore, analysis of the structural models and molecular simulations suggested that the higher affinity for agonists characteristic of the open- and desensitized-channel conformations results, at least in part, from the tighter confinement of the ligand to its binding site;this limits the ligand's fluctuations, and thus delays its escape into bulk solvent.

关键词： Cys-loop receptors structure-function relationships lipid membranes molecular dynamics allosteric proteins

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Investigation of bone matrix composition, architecture and mechanical properties reflect structure-function relationship of cortical bone in glucocorticoid induced osteoporosis

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BONE 2020年 136卷 115334-115334页

作者： Xi, Li Song, Yu Wu, Wenwang Qu, Zhaoliang Wen, Jiawei Liao, Binbin Tao, Ran Ge, Jingran Fang, Daining Beijing Inst Technol Inst Adv Struct Technol Beijing Peoples R China Queen Mary Univ London Sch Engn & Mat Sci London E1 4NS England Diamond Light Source Ltd Beamline I22Harwell Sci & Innovat Campus Didcot Oxon England North Carolina State Univ Coll Text Raleigh NC USA Shanghai Jiao Tong Univ Sch Naval Architecture Ocean & Civil Engn Dept Engn Mech Shanghai 200240 Peoples R China MIT Dept Mech Engn Cambridge MA 02139 USA Univ Moratuwa Dept Mech Engn Moratuwa Sri Lanka Peking Univ Coll Engn State Key Lab Turbulence & Complex Syst Beijing Peoples R China

Glucocorticoid induced osteoporosis (GIOP) is the most common negative consequence of long-term glucocorticoid treatment, leading to increased fracture risk followed by loss of mobility and high mortality risk. These biologically induced changes in bone quality at molecular level lead to changes both in bone matrix architecture and bone matrix composition. However, the quantitative details of changes in bone quality - and especially their link to reduced macroscale mechanical properties are still largely missing. In this study, a mouse model for glucocorticoid-induced osteoporosis (GIOP) was used to investigate mechanical and material alterations in bone cortex (natural nanocomposite) at different scale. By combining quantitative backscattered electron (qBSE) imaging, nanoindentation and high brilliance synchrotron X-ray nanomechanical imaging on a genetically modified mouse model of GIOP, we were able to quantify the local indentation modulus, mineralization distribution and the alterations of nanoscale structures and deformation mechanisms in the mid-diaphysis of femur, and relate them to the macroscopic mechanical changes. Our results showed clear and significant changes in terms of material quality of bone at nanoscale and microscale, which manifests itself in development of spatial heterogeneities in mineralization and indentation moduli across the bone organ, with potential implications for increased fracture risk.

关键词： Glucocorticoid induced osteoporosis structure-function relationships Nanoindentation Synchrotron X-ray nanomechanical imaging

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Scorpion venom phospholipases A2: A minireview

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TOXICON 2020年 184卷 48-54页

作者： Krayem, Najeh Gargouri, Youssef Univ Sfax Lab Biochim & Genie Enzymat Lipases ENIS Route Soukra 3038BP 1173 Sfax Tunisia

Many venomous species, including snakes, bees and scorpions, contain a variety of secreted phospholipases A(2) (sPLA(2)) that contribute to prey digestion and venom toxicity. Based on their primary structures, the different venom sPLA(2) have been classified into four groups I, II, III and IX. While the structure of sPLA(2) groups II and I has been well characterized, only one crystal structure of group III sPLA(2) from bee venom was described. Scorpion venom sPLA(2) belong to group III with a particular heterodimeric structure composed of a long enzymatic chain linked by a disulfide bridge to a Short one after the release of five residues (penta-peptide) during the maturation processes. The function of the Short chain is still not clear. Its sequence varies in composition and in length between different scorpion species. Available studies of the structure-function relationships of scorpion venom sPLA(2) are limited. Some biological activities of these enzymes such as neumtoxicity, myotoxicity, along with the hemolytic, anticoagulant, anti-tumoral and anti-angiogenic activities have been investigated. In this review, we tentatively summarize the last findings about the biochemical properties, the structure-function relation and the biological activities of scorpion venom phospholipases A(2). In addition to expanding the database of structures for these sPLA(2) and understanding their properties and functions, this survey is intended to explore the molecular mechanisms and signaling pathways of the described biological activities.

关键词： Secreted phospholipases A(2) Scorpion venom phospholipases A(2) Biological activities Biochemical properties structure-function relationships

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Design, optimization, and nanotechnology of antimicrobial peptides: From exploration to applications

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NANO TODAY 2021年 39卷 101229-101229页

作者： Tan, Peng Fu, Huiyang Ma, Xi China Agr Univ Coll Anim Sci & Technol State Key Lab Anim Nutr Beijing Peoples R China

Antibiotic resistance caused by antibiotic abuse, especially the emergence of multi-drug resistant bacteria, poses a serious threat to human health, and makes it imperative to find novel antibiotic alternatives. Antimicrobial peptides (AMPs) as a kind of biomaterials have been revolutionarily evolved into formidable candidates due to their unique non-specific membrane rupture mechanism. However, natural AMPs exist a series of problems including weak bioactivity, high toxicity, and immature stability, which seriously hindered their application. Fortunately, in recent years, the progress of molecular design and optimization strategies, and the fast-rising nanotechnology, have shown the potential to improve the biological and chemical properties of AMPs, which make the application of AMPs possible. Herein, we first review the progress in the design and optimization strategies of AMPs, which lay a theoretical foundation for the development of peptide-based antimicrobial nanomaterials and provided more effective antibiotic alternatives. Secondly, we summarized the construction strategy and biological effects of peptide-based antimicrobial nanomaterials. Lastly, the applications of peptide-based antimicrobial drugs were introduced, and the current challenges and future perspectives in this field are proposed. (c) 2021 Elsevier Ltd. All rights reserved.

关键词： Antimicrobial peptides structure-function relationships Nanomaterials Nanotechnology Self-assembly Applications

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Material properties of bighorn sheep (Ovis canadensis) horncore bone with implications for energy absorption during impacts

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JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS 2021年 114卷 104224-104224页

作者： Fuller, Luca H. Donahue, Seth W. Univ Massachusetts Dept Biomed Engn Amherst MA 01003 USA

Bighorn sheep rams participate in high impact head-butting without overt signs of brain injury, thus providing a naturally occurring animal model for studying brain injury mitigation. Previously published finite element modeling showed that both the horn and bone materials play important roles in reducing brain cavity accelerations during ramming. However, in that study the elastic modulus of bone was assumed to be similar to that of human bone since the modulus of ram bone was unknown. Therefore, the goal of this study was to quantify the mechanical properties, mineral content, porosity, and microstructural organization of horncore cortical bone from juvenile and adult rams. Mineral content and elastic modulus increased with horn size, and porosity decreased. However, modulus of toughness did not change with horn size. This latter finding raises the possibility that the horncore cortical bone has not adapted exceptional toughness despite an extreme loading environment and may function primarily as an interface material between the horn and the porous bone within the horncore. Thus, geometric properties of the horn and horncore, including the porous bone architecture, may be more important for energy absorption during ramming than the horncore cortical bone. Results from this study can be used to improve accuracy of finite element models of bighorn sheep ramming to investigate these possibilities moving forward.

关键词： Cortical bone Horncore bone Energy absorption Impact structure-function relationships

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Ready for Screening: Fast Assessable Hydraulic and Anatomical Proxies for Vulnerability to Cavitation of Young Conifer Sapwood

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FORESTS 2021年第8期12卷 1104页

作者： Rosner, Sabine Noebauer, Sebastian Voggeneder, Klara BOKU Univ Vienna Inst Bot Gregor Mendel Str 33 A-1180 Vienna Austria

Research Highlights: novel fast and easily assessable proxies for vulnerability to cavitation of conifer sapwood are proposed that allow reliable estimation at the species level. Background and Objectives: global warming calls for fast and easily applicable methods to measure hydraulic vulnerability in conifers since they are one of the most sensitive plant groups regarding drought stress. Classical methods to determine P-12, P-50 and P-88, i.e., the water potentials resulting in 12, 50 and 88% conductivity loss, respectively, are labour intensive, prone to errors and/or restricted to special facilities. Vulnerability proxies were established based on empirical relationships between hydraulic traits, basic density and sapwood anatomy. Materials and Methods: reference values for hydraulic traits were obtained by means of the air injection method on six conifer species. Datasets for potential P-50 proxies comprised relative water loss (RWL), basic density, saturated water content as well as anatomical traits such as double wall thickness, tracheid lumen diameter and wall/lumen ratio. Results: our novel proxy P-25W, defined as 25% RWL induced by air injection, was the most reliable estimate for P-50 (r = 0.95) and P-88 (r = 0.96). Basic wood density (r = -0.92), tangential lumen diameters in earlywood (r = 0.88), wall/lumen ratios measured in the tangential direction (r = -0.86) and the number of radial cell files/mm circumference (CF/mm, r = -0.85) were also strongly related to P-50. Moreover, CF/mm was a very good predictor for P-12 (r = -0.93). Conclusions: the proxy P-25W is regarded a strong phenotyping tool for screening conifer species for vulnerability to cavitation assuming that the relationship between RWL and conductivity loss is robust in conifer sapwood. We also see a high potential for the fast and easily applicable proxy CF/mm as a screening tool for drought sensitivity and for application in dendroecological studies that investigate forest dieback.

关键词： conifers biodiversity drought stress forest dieback hydraulic capacitance phenotyping structure-function relationships vulnerability to cavitation wood anatomy

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Effect of salt addition on iota-carrageenan solution properties

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FOOD HYDROCOLLOIDS 2021年 113卷 106491-106491页

作者： Elfaruk, Mohamed Salem Wen, Chengrong Chi, Chengdeng Li, Xiaoxi Janaswamy, Srinivas South Dakota State Univ Dept Dairy & Food Sci Brookings SD 57007 USA Nalut Univ Med Technol Coll Nalut 00218 Libya Dalian Polytech Univ Sch Food Sci & Technol Natl & Local Joint Engn Lab Marine Bioact Polysac Natl Engn Res Ctr Seafood Dalian 116034 Peoples R China South China Univ Technol Sch Food Sci & Engn Guangdong Prov Key Lab Green Proc Nat Prod & Prod Minist EducEngn Res Ctr Starch & Prot Proc Guangzhou 510640 Peoples R China

Polysaccharides are versatile biopolymers available to mankind for multiple uses ranging from achieving desirable food texture to serving as tissue scaffolds. Their complete utility, however, is yet unrealized by the lack of precise knowledge on their structure function relationships. Herein, sodium iota-carrageenan (IC) is selected as a model polysaccharide and its viscoelastic properties, molecular assembly, water mobility, microstructure and melting behavior have been analyzed to understand the salt effect. Results demonstrate that while the storage modulus, gel-sol transition temperature, thermal stability and helical aggregation increase, water mobility decreases, with salt addition;the initial no-salt IC ordered microstructure transforms to an irregular structure composed of larger cavities. These observations are intimately associated with the dynamic interactions persistent at the molecular level between the anionic IC chains and salt ions. Overall, results help to move a step closer to realize the functional behavior of iota-carrageenan and by extrapolation to other polysaccharides as well.

关键词： Viscoelastic properties Synergistic interactions Thermal properties Microstructure Water mobility SAXS structure-function relationships

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Development of a standardized histopathology scoring system using machine learning algorithms for intervertebral disc degeneration in the mouse model-An ORS spine section initiative

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JOR SPINE 2021年第2期4卷 e1164页

作者： Melgoza, Itzel Paola Chenna, Srish S. Tessier, Steven Zhang, Yejia Tang, Simon Y. Ohnishi, Takashi Novais, Emanuel Jose Kerr, Geoffrey J. Mohanty, Sarthak Tam, Vivian Chan, Wilson C. W. Zhou, Chao-Ming Zhang, Ying Leung, Victor Y. Brice, Angela K. Seguin, Cheryle A. Chan, Danny Vo, Nam Risbud, Makarand V. Dahia, Chitra L. Hosp Special Surg Orthoped Soft Tissue Res Program 535 E 70th St New York NY 10021 USA Weill Cornell Med Grad Sch Med Sci Dept Cell & Dev Biol New York NY USA Thomas Jefferson Univ Sidney Kimmel Med Coll Dept Orthopaed Surg Philadelphia PA 19107 USA Univ Penn Philadelphia PA 19104 USA Washington Univ Dept Orthopaed Surg St Louis MO 63110 USA Hokkaido Univ Fac Med Dept Orthopaed Surg Sapporo Hokkaido Japan Hokkaido Univ Grad Sch Med Sapporo Hokkaido Japan Temple Univ Lewis Katz Sch Med Philadelphia PA 19122 USA Univ Western Ontario Bone & Joint Inst Dept Physiol & Pharmacol London ON Canada Univ Hong Kong Sch Biomed Sci Pokfulam Hong Kong Peoples R China Univ Hong Kong Shenzhen Hosp Dept Orthopaed & Traumatol Shenzhen Guangdong Peoples R China Univ Pittsburgh Dept Orthopaed Surg Pittsburgh PA 15260 USA Univ Hong Kong Dept Orthopaed & Traumatol Pokfulam Hong Kong Peoples R China

Mice have been increasingly used as preclinical model to elucidate mechanisms and test therapeutics for treating intervertebral disc degeneration (IDD). Several intervertebral disc (IVD) histological scoring systems have been proposed, but none exists that reliably quantitate mouse disc pathologies. Here, we report a new robust quantitative mouse IVD histopathological scoring system developed by building consensus from the spine community analyses of previous scoring systems and features noted on different mouse models of IDD. The new scoring system analyzes 14 key histopathological features from nucleus pulposus (NP), annulus fibrosus (AF), endplate (EP), and AF/NP/EP interface regions. Each feature is categorized and scored;hence, the weight for quantifying the disc histopathology is equally distributed and not driven by only a few features. We tested the new histopathological scoring criteria using images of lumbar and coccygeal discs from different IDD models of both sexes, including genetic, needle-punctured, static compressive models, and natural aging mice spanning neonatal to old age stages. Moreover, disc sections from common histological preparation techniques and stains including H&E, SafraninO/Fast green, and FAST were analyzed to enable better cross-study comparisons. Fleiss's multi-rater agreement test shows significant agreement by both experienced and novice multiple raters for all 14 features on several mouse models and sections prepared using various histological techniques. The sensitivity and specificity of the new scoring system was validated using artificial intelligence and supervised and unsupervised machine learning algorithms, including artificial neural networks, k-means clustering, and principal component analysis. Finally, we applied the new scoring system on established disc degeneration models and demonstrated high sensitivity and specificity of histopathological scoring changes. Overall, the new histopathological scoring system offers

关键词： aging degeneration pre-clinical models structure-function relationships

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Abstract 1807 Polybromo-1 bromodomain missense variants associated with clear cell renal cell carcinoma exhibit variable biochemical fitness

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Journal of Biological Chemistry 2025年第5期301卷

作者： Karina Bursch Salomão Jorge Audrey Catlin Jacob Licklider Raul Urrutia Brian Smith Medical College of Wisconsin

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