Health-related quality of life and healthcare costs of symptoms and cardiovascular disease events in patients with atrial fibrillation: a longitudinal analysis of 27 countries from the EURObservational Research Programme on Atrial Fibrillation general long-term registry.

AIMS: We examine the effects of symptoms and cardiovascular disease (CVD) events on health-related quality of life (HRQOL) and healthcare costs in a European population with atrial fibrillation (AF). METHODS AND RESULTS: In the EURObservational Research Programme on AF long-term general registry, AF patients from 250 centres in 27 European countries were enrolled and followed for 2 years. We used fixed effects models to estimate the association of symptoms and CVD events on HRQOL and annual healthcare costs. We found significant decrements in HRQOL in AF patients in whom ST-segment elevation myocardial infarction (STEMI) [-0.075 (95% confidence interval -0.144, -0.006)], angina or non-ST-elevation myocardial infarction (NSTEMI) [-0.037 (-0.071, -0.003)], new-onset/worsening heart failure [-0.064 (-0.088, -0.039)], bleeding events [-0.031 (-0.059, -0.003)], thromboembolic events [-0.071 (-0.115, -0.027)], mild symptoms [0.037 (-0.048, -0.026)], or severe/disabling symptoms [-0.090 (-0.108, -0.072)] occurred during the follow-up. During follow-up, annual healthcare costs were associated with an increase of €11 718 (€8497, €14 939) in patients with STEMI, €5823 (€4757, €6889) in patients with angina/NSTEMI, €3689 (€3219, €4158) in patients with new-onset or worsening heart failure, €3792 (€3315, €4270) in patients with bleeding events, and €3182 (€2483, €3881) in patients with thromboembolic events, compared with AF patients without these events. Healthcare costs were primarily driven by inpatient costs. There were no significant differences in HRQOL or healthcare resource use between EU regions or by sex. CONCLUSION: Symptoms and CVD events are associated with a high burden on AF patients and healthcare systems throughout Europe.

Economic burden of cardiovascular diseases in the European Union: a population-based cost study.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) impacts significantly health and social care systems as well as society through premature mortality and disability, with patients requiring care from relatives. Previous pan-European estimates of the economic burden of CVD are now outdated. This study aims to provide novel, up-to-date evidence on the economic burden across the 27 European Union (EU) countries in 2021. METHODS: Aggregate country-specific resource use data on morbidity, mortality, and health, social and informal care were obtained from international sources, such as the Statistical Office of the European Communities, enhanced by data from the European Society of Cardiology Atlas programme and patient-level data from the Survey of Health, Ageing and Retirement in Europe. Country-specific unit costs were used, with cost estimates reported on a per capita basis, after adjustment for price differentials. RESULTS: CVD is estimated to cost the EU €282 billion annually, with health and long-term care accounting for €155 billion (55%), equalling 11% of EU-health expenditure. Productivity losses accounted for 17% (€48 billion), whereas informal care costs were €79 billion (28%). CVD represented a cost of €630 per person, ranging from €381 in Cyprus to €903 in Germany. Coronary heart disease accounted for 27% (€77 billion) and cerebrovascular diseases for 27% (€76 billion) of CVD costs. CONCLUSIONS: This study provides contemporary estimates of the wide-ranging impact of CVD on all aspects of the economy. The data help inform evidence-based policies to reduce the impact of CVD, promoting care access and better health outcomes and economic sustainability.

European Society of Cardiology: cardiovascular disease statistics 2021.

AIMS: This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the widely cited 2019 report in presenting cardiovascular disease (CVD) statistics for the 57 ESC member countries. METHODS AND RESULTS: Statistics pertaining to 2019, or the latest available year, are presented. Data sources include the World Health Organization, the Institute for Health Metrics and Evaluation, the World Bank, and novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery. New material in this report includes sociodemographic and environmental determinants of CVD, rheumatic heart disease, out-of-hospital cardiac arrest, left-sided valvular heart disease, the advocacy potential of these CVD statistics, and progress towards World Health Organization (WHO) 2025 targets for non-communicable diseases. Salient observations in this report: (i) Females born in ESC member countries in 2018 are expected to live 80.8 years and males 74.8 years. Life expectancy is longer in high income (81.6 years) compared with middle-income (74.2 years) countries. (ii) In 2018, high-income countries spent, on average, four times more on healthcare than middle-income countries. (iii) The median PM2.5 concentrations in 2019 were over twice as high in middle-income ESC member countries compared with high-income countries and exceeded the EU air quality standard in 14 countries, all middle-income. (iv) In 2016, more than one in five adults across the ESC member countries were obese with similar prevalence in high and low-income countries. The prevalence of obesity has more than doubled over the past 35 years. (v) The burden of CVD falls hardest on middle-income ESC member countries where estimated incidence rates are ∼30% higher compared with high-income countries. This is reflected in disability-adjusted life years due to CVD which are nearly four times as high in middle-income compared with high-income countries. (vi) The incidence of calcific aortic valve disease has increased seven-fold during the last 30 years, with age-standardized rates four times as high in high-income compared with middle-income countries. (vii) Although the total number of CVD deaths across all countries far exceeds the number of cancer deaths for both sexes, there are 15 ESC member countries in which cancer accounts for more deaths than CVD in males and five-member countries in which cancer accounts for more deaths than CVD in females. (viii) The under-resourced status of middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, ablation procedures, device implantation, and cardiac surgical procedures. CONCLUSION: Risk factors and unhealthy behaviours are potentially reversible, and this provides a huge opportunity to address the health inequalities across ESC member countries that are highlighted in this report. It seems clear, however, that efforts to seize this opportunity are falling short and present evidence suggests that most of the WHO NCD targets for 2025 are unlikely to be met across ESC member countries.

New Way to "SCORE" Risk: Updates on the ESC Scoring System and Incorporation into ESC Cardiovascular Prevention Guidelines.

PURPOSE OF REVIEW: Prior European Society of Cardiology (ESC) guidelines endorsed the SCORE 10-year cardiovascular disease (CVD) risk calculator to inform the total risk approach to CVD prevention, including the use of preventive interventions like lipid lowering therapies. However, SCORE was released in 2003, did not allow for estimation of fatal and non-fatal CVD events, and was limited to adults aged 40 to 70 years. The ESC's Cardiovascular Risk Collaboration (CRC) was tasked with updating SCORE (SCORE2) and with extending the upper age range of adults eligible for risk estimation (SCORE2-OP). This review summarises these two deliverables. RECENT FINDINGS: Published in 2021, these updated risk scores allow for estimation of 10 year total (fatal + non-fatal) risks of a first atherosclerotic cardiovascular event in adults (SCORE2) and older persons (SCORE2-OP), calibrated for use in four European risk regions. The models account for competing risk of non-CVD death. These were extensively validated with excellent calibration and C-statistics ranging from 0.67 to 0.81. SCORE2 and SCORE2-OP have informed the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. In addition to endorsing these two updated risk calculators, these guidelines have, for the first time, recommended the use of age-related risk categories. This change was motivated to prevent overreliance on age when making CVD prevention decisions.

Mapping interventional cardiology in Europe: the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Atlas Project.

AIMS: The European Association of Percutaneous Cardiovascular Interventions (EAPCI) Atlas of Interventional Cardiology has been developed to map interventional practice across European Society of Cardiology (ESC) member countries. Here we present the main findings of a 16-country survey in which we examine the national availability of interventional infrastructure, human resource, and procedure volumes. METHODS AND RESULTS: Sixteen ESC member countries participated in the EAPCI Atlas survey. Interventional data were collected by the National Cardiac Society of each participating country. An annual median of 5131 [interquartile range (IQR) 4013-5801] diagnostic heart procedures per million people were reported, ranging from <2500 in Egypt and Romania to >7000 in Turkey and Germany. Procedure rates showed significant correlation (r = 0.67, P = 0.013) with gross national income (GNI) per capita. An annual median of 2478 (IQR 1690-2633) percutaneous coronary interventions (PCIs) per million people were reported, ranging from <1000 in Egypt and Romania to >3000 in Switzerland, Poland, and Germany. Procedure rates showed significant correlation with GNI per capita (r = 0.62, P = 0.014). An annual median of 48.2 (IQR 29.1-105.2) transcatheter aortic valve implantation procedures per million people were performed, varying from <25 per million people in Egypt, Romania, Turkey, and Poland to >100 per million people in Denmark, France, Switzerland, and Germany. Procedure rates showed significant correlation with national GNI per capita (r = 0.92, P < 0.001). CONCLUSION: The first report from the EAPCI Atlas has shown considerable international heterogeneity in interventional cardiology procedure volumes. The heterogeneity showed association with national economic resource, a reflection no doubt of the technological costs of developing an interventional cardiology service.

European Society of Cardiology: Cardiovascular Disease Statistics 2019.

AIMS: The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. METHODS AND RESULTS: In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5-23.1%] vs. 15.7% (IQR 14.5-21.1%)}, diabetes [7.7% (IQR 7.1-10.1%) vs. 5.6% (IQR 4.8-7.0%)], and among males smoking [43.8% (IQR 37.4-48.0%) vs. 26.0% (IQR 20.9-31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0-10.8) vs. 16.7% (IQR 13.9-19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655-8115)] compared with high-income [2235 (IQR 1896-3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. CONCLUSION: A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.

Cardiovascular disease burden due to productivity losses in European Society of Cardiology countries.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death across Europe. We estimated lost earnings (productivity losses) associated with premature mortality due to CVD, and separately for its main sub-categories of coronary heart disease and cerebrovascular disease, across 54 country members of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used a standardized approach to estimate working years and earnings lost due to premature death resulting from CVD across the 54 ESC member countries in 2018. Our population-based approach was based on national data on the number of deaths, employment rates, and earnings by age group and sex. We discounted future working years and earnings lost to present values using a 3.5% annual rate. In 2018, there were 4.4 million deaths due to CVD across the 54 countries, with 7.1 million working years lost. This represented productivity losses due to premature death of €62 billion in 2018. Deaths due to coronary heart disease accounted for 47% (€29 billion) of all CVD costs, and cerebrovascular disease accounted for 18% (€11 billion). Approximately 60% (€37 billion) of all productivity losses occurred in the 28 European Union member states, despite accounting for only 42% (1.8 million) of deaths and 21% (1.5 million) of working years lost across the 54 countries. CONCLUSION: Our study provides a snapshot of the economic consequences posed by premature mortality due to CVD across 54 countries in 2018. The considerable variation across countries highlights the potential gains from policies targeting prevention and care of cardiovascular diseases.

Global epidemiology of acute coronary syndromes.

This Review provides an epidemiological overview of global mortality from acute coronary syndromes (ACS). Across the regions of the world where data are available, mortality from ACS - including premature (age <70 years) mortality from ACS - was higher in men than in women. In both sexes, age-standardized mortality rates (ASMRs) for ACS in 2020 were highest in lower-income global regions. However, 20 years earlier, ASMRs for ACS were highest in higher-income global regions, including Europe, Northern America and Oceania. These higher-income regions have seen progressive reductions in mortality from ACS during the past 20 years, which is in contrast to the more stable levels of mortality from ACS in Asia and in Latin America and the Caribbean. In the seven African countries with data available, a small upwards trend in ASMRs for ACS was observed, reflecting an epidemiological transition that is already well advanced in these regions. Consistent with these changes during the past 20 years were >50% reductions in ASMRs for ACS in the high-income countries of the world compared with <15% reductions in lower-middle-income countries. Policymakers need more complete epidemiological data across and within global regions to identify those countries in which the burden of death from ACS is greatest and the need to implement preventive strategies is most pressing.

Cardiovascular disease care and outcomes in West and South European countries.

Variations in cardiovascular disease (CVD) burden between West and South European countries are rarely reported. To address this knowledge gap, The Lancet Regional Health-Europe convened experts from a broad range of countries to assess the current state of knowledge of cardiovascular disease inequalities across Europe. This Review is specifically focused on West and South European countries. Mortality, risk factor and economic data for nine West European and six South European countries were sourced from the World Health Organisation, the Global Burden of Disease study and the World Bank. Healthcare data were collected by survey of participating countries. A key finding was of declines in age-standardised mortality rates (ASMRs) across all countries since 1990. In 2019 rates per 100,000 were lower in West European countries in males (279.7 (264.1-335.9) vs 337.2 (323.7-367.2)) and females (196.2 (183.3-228.8) vs 247.3 (232.2-268.3)). Differences in risk factor exposures were small, with the exception of physical activity and dietary factors, but across all countries the prevalence of obesity has increased, affecting >20% of adults in 2019. Healthcare delivery in 2019 showed inequalities with cardiovascular procedure rates lower in South compared with West European countries. Further declines in ASMRs in West and South European countries will require population strategies to reduce obesity and address inequalities in physical activity and dietary factors. Reducing the gap in procedure rates is unlikely to match the beneficial effects of population strategies for reducing CVD burden in South European countries.

Purification, crystallization and preliminary X-ray diffraction analysis of the Fyn SH2 domain and its complex with a phosphotyrosine peptide.

SH2 domains are widespread protein-binding modules that recognize phosphotyrosines and play central roles in intracellular signalling pathways. The SH2 domain of the human protein tyrosine kinase Fyn has been expressed, purified and crystallized in the unbound state and in complex with a high-affinity phosphotyrosine peptide. X-ray data were collected to a resolution of 2.00 Å for the unbound form and 1.40 Å for the protein in complex with the phosphotyrosine peptide.

Epidemiology of cardiovascular disease in Europe.

This Review presents data describing the health burden of cardiovascular disease (CVD) within and across the WHO European Region. CVD remains the most common cause of death in the region. Deaths from CVD in those aged <70 years, commonly referred to as premature, are a particular concern, with >60 million potential years of life lost to CVD in Europe annually. Although more women than men die from CVD, age-standardized rates of both morbidity and death are higher in men, and these differences in rates are greatest in individuals aged <70 years. Large inequalities in all measures of morbidity, treatment and mortality can be found between countries across the continent and must be a focus for improving health. Large differences also exist in the data available between countries. The development and implementation of evidence-based preventive and treatment approaches must be supported in all countries by consistent surveillance and monitoring, such that we can quantify the health burden of CVD as well as target interventions and provide impetus for action across Europe.

European Society of Cardiology: cardiovascular disease statistics 2021: Executive Summary.

AIMS: This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the widely cited 2019 report in presenting cardiovascular disease (CVD) statistics for the 57 ESC member countries. METHODS AND RESULTS: Statistics pertaining to 2019, or the latest available year, are presented. Data sources include the World Health Organization, the Institute for Health Metrics and Evaluation, the World Bank, and novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery. New material in this report includes sociodemographic and environmental determinants of CVD, rheumatic heart disease, out-of-hospital cardiac arrest, leftsided valvular heart disease, the advocacy potential of these CVD statistics, and progress towards World Health Organization (WHO) 2025 targets for non-communicable diseases. Salient observations in this report: (i) Females born in ESC member countries in 2018 are expected to live 80.8 years and males 74.8 years. Life expectancy is longer in high income (81.6 years) compared with middle-income (74.2 years) countries. (ii) In 2018, high-income countries spent, on average, four times more on healthcare than middle-income countries. (iii) The median PM2.5 concentrations in 2019 were over twice as high in middle-income ESC member countries compared with high-income countries and exceeded the EU air quality standard in 14 countries, all middle-income. (iv) In 2016, more than one in five adults across the ESC member countries were obese with similar prevalence in high and low-income countries. The prevalence of obesity has more than doubled over the past 35 years. (v) The burden of CVD falls hardest on middle-income ESC member countries where estimated incidence rates are ∼30% higher compared with high-income countries. This is reflected in disability-adjusted life years due to CVD which are nearly four times as high in middle-income compared with high-income countries. (vi) The incidence of calcific aortic valve disease has increased seven-fold during the last 30 years, with age-standardized rates four times as high in high-income compared with middle-income countries. (vii) Although the total number of CVD deaths across all countries far exceeds the number of cancer deaths for both sexes, there are 15 ESC member countries in which cancer accounts for more deaths than CVD in males and five-member countries in which cancer accounts for more deaths than CVD in females. (viii) The under-resourced status of middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, ablation procedures, device implantation, and cardiac surgical procedures. CONCLUSION: Risk factors and unhealthy behaviours are potentially reversible, and this provides a huge opportunity to address the health inequalities across ESC member countries that are highlighted in this report. It seems clear, however, that efforts to seize this opportunity are falling short and present evidence suggests that most of the WHO NCD targets for 2025 are unlikely to be met across ESC member countries.

Systematic Coronary Risk Evaluation (SCORE): JACC Focus Seminar 4/8.

Clinical estimation of the combined effect of several risk factors is unreliable and this resulted in the development of a number of risk estimation systems to guide clinical practice. Here, after defining general principles of risk estimation, the authors describe the evolution of the European Society of Cardiology's (ESC) Systematic COronary Risk Evaluation (SCORE) risk estimation system and some learnings from the data. They move on to describe the establishment of the ESC's Cardiovascular Risk Collaboration and outline its proposed research directions. First among these is the evolution of SCORE 2, which provides updated, calibrated risk estimates for total cardiovascular events for low, moderate, high, and very high-risk regions of Europe. The authors conclude by considering that the future of risk estimation may be to express risk as years of exposure to a cardiovascular risk factor profile rather than risk over a fixed time period, such as 10 years, and how advances in genetics may permit individualized lifetime risk estimation from childhood on.

The Heart Failure Association Atlas: Heart Failure Epidemiology and Management Statistics 2019.

AIMS: The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) developed the HFA Atlas to provide a contemporary description of heart failure (HF) epidemiology, resources, reimbursement of guideline-directed medical therapy (GDMT) and activities of the National Heart Failure Societies (NHFS) in ESC member countries. METHODS AND RESULTS: The HFA Atlas survey was conducted in 2018-2019 in 42 ESC countries. The quality and completeness of source data varied across countries. The median incidence of HF was 3.20 [interquartile range (IQR) 2.66-4.17] cases per 1000 person-years, ranging from ≤2 in Italy and Denmark to >6 in Germany. The median HF prevalence was 17.20 (IQR 14.30-21) cases per 1000 people, ranging from ≤12 in Greece and Spain to >30 in Lithuania and Germany. The median number of HF hospitalizations was 2671 (IQR 1771-4317) per million people annually, ranging from <1000 in Latvia and North Macedonia to >6000 in Romania, Germany and Norway. The median length of hospital stay for an admission with HF was 8.50 (IQR 7.38-10) days. Diagnostic and management resources for HF varied, with high-income ESC member countries having substantially more resources compared with middle-income countries. The median number of hospitals with dedicated HF centres was 1.16 (IQR 0.51-2.97) per million people, ranging from <0.10 in Russian Federation and Ukraine to >7 in Norway and Italy. Nearly all countries reported full or partial reimbursement of standard GDMT, except ivabradine and sacubitril/valsartan. Almost all countries reported having NHFS or working groups and nearly half had HF patient organizations. CONCLUSIONS: The first report from the HFA Atlas has shown considerable heterogeneity in HF disease burden, the resources available for its management and data quality across ESC member countries. The findings emphasize the need for a systematic approach to the capture of HF statistics so that inequalities and improvements in care may be quantified and addressed.

The Heart Failure Association Atlas: rationale, objectives, and methods.

Heart failure (HF) constitutes the growing cardiovascular burden and the major public health issue, but comprehensive statistics on HF epidemiology and related management in Europe are missing. The Heart Failure Association (HFA) Atlas has been initiated in 2016 in order to close this gap, representing the continuity directly rooted in the European Society of Cardiology (ESC) Atlas of Cardiology. The major aim of the HFA Atlas is to establish a contemporary dataset on HF epidemiology, resources and reimbursement policies for HF management, organization of the National Heart Failure Societies (NHFS) and their major activities, including education and HF awareness. These data are gathered in collaboration with the network of NHFS of the ESC member and ESC affiliated countries. The dataset will be continuously improved and advanced based on the experience and enhanced understanding of data collection in the forthcoming years. This will enable revealing trends, disparities and gaps in knowledge on epidemiology and management of HF. Such data are highly needed by the clinicians of different specialties (aside from cardiologists and cardiac surgeons), researchers, healthcare policy makers, as well as HF patients and their caregivers. It will also allow to map the snapshot of realities in HF care, as well as to provide insights for evidence-based health care policy in contemporary management of HF. Such data will support the ESC/HFA efforts to improve HF management ant outcomes through stronger recommendations and calls for action. This will likely influence the allocation of funds for the prevention, treatment, education and research in HF.

Malathion-induced alteration of the antioxidant defence system in kidney, gill, and intestine of Carassius auratus gibelio.

Pesticides such as malathion, commonly used in agriculture and households, are toxic substances that lead to reactive oxygen species generation, which harms organisms. Ecotoxicological consequences of malathion, particularly its effects on antioxidants in fish, are not well understood. Thus, we investigated the effects of malathion (0.05 mg/L) on lipid peroxidation and antioxidant systems in Carassius auratus gibelio kidney, intestine, and gills following exposure times of 1, 2, 3, and 6 days. The lipid peroxidation and antioxidative defense mechanisms display different responses in investigated tissues. The lipid peroxidation was increased in all investigated tissues, especially after 1 day of malathion administration. Changes in reduced glutathione levels have been registered, mainly after 6 days of pesticide exposure. The modulation in the activities of antioxidant enzymes, catalase, gluthatione peroxidase, glutathione reductase, and glutathione-S-transferase was time and tissue specific. The investigated parameters can be used as biomarkers of fish exposure to malathion.

Structural Characterization of Monomeric/Dimeric State of p59fyn SH2 Domain.

Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59fyn SH2 domain.

Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.

Src kinase activity is controlled by various mechanisms involving a coordinated movement of kinase and regulatory domains. Notwithstanding the extensive knowledge related to the backbone dynamics, little is known about the more subtle side-chain dynamics within the regulatory domains and their role in the activation process. Here, we show through experimental methyl dynamic results and predicted changes in side-chain conformational couplings that the SH2 structure of Fyn contains a dynamic network capable of propagating binding information. We reveal that binding the phosphorylated tail of Fyn perturbs a residue cluster near the linker connecting the SH2 and SH3 domains of Fyn, which is known to be relevant in the regulation of the activity of Fyn. Biochemical perturbation experiments validate that those residues are essential for inhibition of Fyn, leading to a gain of function upon mutation. These findings reveal how side-chain dynamics may facilitate the allosteric regulation of the different members of the Src kinase family.

Structural insights into the intertwined dimer of fyn SH2.

Src homology 2 domains are interaction modules dedicated to the recognition of phosphotyrosine sites incorporated in numerous proteins found in intracellular signaling pathways. Here we provide for the first time structural insight into the dimerization of Fyn SH2 both in solution and in crystalline conditions, providing novel crystal structures of both the dimer and peptide-bound structures of Fyn SH2. Using nuclear magnetic resonance chemical shift analysis, we show how the peptide is able to eradicate the dimerization, leading to monomeric SH2 in its bound state. Furthermore, we show that Fyn SH2's dimer form differs from other SH2 dimers reported earlier. Interestingly, the Fyn dimer can be used to construct a completed dimer model of Fyn without any steric clashes. Together these results extend our understanding of SH2 dimerization, giving structural details, on one hand, and suggesting a possible physiological relevance of such behavior, on the other hand.

¹H, ¹³C and ¹5N backbone and side-chain chemical shift assignments of the free and bound forms of the human PTPN11 second SH2 domain.

Src homology 2 (SH2) domains have an important role in the regulation of protein activity and intracellular signaling processes. They are geared to bind to specific phosphotyrosine (pY) motifs, with a substrate sequence specificity depending on the three amino acids immediately C-terminal to the pY. Here we report for the first time the (1)H, (15)N and (13)C backbone and side-chain chemical shift assignments for the C-terminal SH2 domain of the human protein tyrosine phosphatase PTPN11, both in its free and bound forms, where the ligand in the latter corresponds to a specific sequence of the human erythropoietin receptor.