Eukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation, and chromatin modifications. Here we examined the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While the AD function of both factors depended on hydrophobic residues, Ino2 further required key conserved acidic and polar residues for optimal function. Binding studies showed that the ADs bound multiple Med15 activator-binding domains (ABDs) with similar orders of micromolar affinity and similar but distinct thermodynamic properties. Protein cross-linking data show that no unique complex was formed upon Met4-Med15 binding. Rather, we observed heterogeneous AD-ABD contacts with nearly every possible AD-ABD combination. Many of these properties are similar to those observed with yeast activator Gcn4, which forms a large heterogeneous, dynamic, and fuzzy complex with Med15. We suggest that this molecular behavior is common among eukaryotic activators.
The survey results on the healthcare and psychosocial experiences from birth through adulthood of individuals with CFM reinforce the need for ongoing psychological assessment and intervention. Healthcare provision could be improved through establishing diagnostic criteria and standardized treatment guidelines, as well as continued investigation of CFM etiology.
This study describes stressors, resources, and recommendations related to craniofacial microsomia (CFM) care from the perspective of caregivers of children with CFM and adults with CFM in order to inform improved quality of healthcare delivery. A mixed method design was used with fixed-response and open-ended questions from an online survey in English. The survey included demographics, CFM phenotypic information, and items about CFM-related experiences across settings. Themes were identified by qualitative analysis of responses to open-ended questions. Respondents (N = 51) included caregivers (n = 42; 90% mothers) and adults with CFM (n = 9; 78% female), who had a mean age of 45±6 years. Most children were male (71%) with an average age of 7±4 years. Respondents were primarily white (80%), non-Hispanic (89%), from the United States (82%), had a college degree (80%), and had private health insurance (80%). Reflecting the high rate of microtia (84%) in the sample, themes centered on the impact of hearing difficulties across settings with related language concerns. Negative social experiences were frequently described and school needs outlined. Multiple medical stressors were identified and corresponding suggestions included: providers need to be better informed about CFM, treatment coordination among specialists, and preference for a family-centered approach with reassurance, empathy, and clear communication. Advice offered to others with CFM included positive coping strategies. Overall, caregivers’ and patients’ responses reflected the complexity of CFM treatment. Incorporating these perspectives into routine CFM care has the potential to reduce family distress while improving their healthcare.
Eukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation and chromatin modifications. Here we examine the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While AD function from both factors depends on hydrophobic residues, Ino2 further requires key conserved acidic and polar residues for optimal function. Binding studies show that the ADs bind multiple Med15 activator binding domains (ABDs) with a similar order of micromolar affinity, and similar but distinct thermodynamic properties. Protein crosslinking shows that no unique complex is formed upon Met4-Med15 binding. Rather, we observed heterogeneous AD-ABD contacts with nearly every possible AD-ABD combination. Many of these properties are similar to those observed with the yeast activator Gcn4, which forms a large heterogeneous, dynamic, and fuzzy complex with Med15. We suggest that this molecular behavior is common among eukaryotic activators.
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