The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase

We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop

Probing Molecular Mechanisms of the Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators of Functional Dynamics

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based “conformational selection” of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients

Consensus on core phenomena and statements describing Basic Body Awareness Therapy within the movement awareness domain in physiotherapy

Physiotherapists are facing complex health challenges in the treatment of persons suffering from long-lasting musculoskeletal disorders and mental health problems. Basic Body Awareness Therapy (BBAT) is a physiotherapy approach within the movement awareness domain developed to bridge physical, mental, and relational health challenges. The purpose of this study was to reach a consensus on core phenomena and statements describing BBAT. A consensus-building process was conducted using the nominal group technique (NGT). Twenty-one BBAT experts from 10 European countries participated in a concentrated weekend workshop of 20 hours. All participants signed informed consent. Participants reached a consensus on 138 core phenomena, clustered in three overarching categories: clinical core, historical roots, and research and evaluation phenomena. Of the 106 clinical core phenomena, the participants agreed on three categories of phenomena: movement quality, movement awareness practice, and movement awareness therapy and pedagogy. Furthermore, the participants reached 100 percent consensus on 16 of 30 statements describing BBAT. This study provides a consensus on core phenomena and statements describing BBAT. The data reveal phenomena implemented when promoting movement quality through movement awareness. Data provide clarity in some aspects of the vocabulary as fundamental theory. Further reearch will be developed

'Girls need to strengthen each other as a group' : experiences from a gender-sensitive stress management intervention by youth-friendly Swedish health services: a qualitative study

Mental health problems among young people, and girls and young women in particular, are a well-known health problem. Such gendered mental health patterns are also seen in conjunction with stress-related problems, such as anxiety and depression and psychosomatic complaints. Thus, intervention models tailored to the health care situation experienced by young women within a gendered and sociocultural context are needed. This qualitative study aims to illuminate young women's experiences of participating in a body-based, gender-sensitive stress management group intervention by youth-friendly health services in northern Sweden. A physiotherapeutic body-based, health-promoting, gender-sensitive stress management intervention was created by youth-friendly Swedish health services. The stress management courses (n = 7) consisted of eight sessions, each lasting about two hours, and were led by the physiotherapist at the youth centre. The content in the intervention had a gender-sensitive approach, combining reflective discussions; short general lectures on, for example, stress and pressures related to body ideals; and physiotherapeutic methods, including body awareness and relaxation. Follow-up interviews were carried out with 32 young women (17--25 years of age) after they had completed the intervention. The data were analysed with qualitative content analysis. The overall results of our interview analysis suggest that the stress management course we evaluated facilitated 'a space for gendered and embodied empowerment in a hectic life', implying that it both contributed to a sense of individual growth and allowed participants to unburden themselves of stress problems within a trustful and supportive context. Participants' narrated experiences of 'finding a social oasis to challenge gendered expectations', 'being bodily empowered', and 'altering gendered positions and stance to life' point to empowering processes of change that allowed them to cope with distress, despite sometimes continuously stressful life situations. This intervention also decreased stress-related symptoms such as anxiousness, restlessness, muscle tension, aches and pains, fatigue, and impaired sleep. The participants' experiences of the intervention as a safe and exploratory space for gendered collective understanding and embodied empowerment further indicates the need to develop gender-sensitive interventions to reduce individualisation of health problems and instead encourage spaces for collective support, action, and change.Stress and Health in Youth (Umeå SHY