Dataset Information

Finding a fitting shoe for Cinderella: searching for an autophagy inhibitor.

ABSTRACT: Vps34 is the ancestral phosphatidylinositol 3-kinase (PtdIns3K) isoform and is essential for endosomal trafficking of proteins to the vacuole/lysosome, autophagy and phagocytosis. Vps34-containing complexes associate with specific cellular compartments to produce PtdIns(3)P. Understanding the roles of Vps34 has been hampered by the lack of potent, specific inhibitors. To boost development of Vps34 inhibitors, we determined the crystal structures of Vps34 alone and in complexes with multitargeted PtdIns3K inhibitors. These structures provided a first glimpse into the uniquely constricted ATP-binding site of Vps34 and enabled us to model Vps34 regulation. We showed that the substrate-binding "activation" loop and the flexibly attached amphipathic C-terminal helix are crucial for catalysis on membranes. The C-terminal helix also suppresses ATP hydrolysis in the absence of membranes. We propose that membrane binding shifts the C-terminal helix to orient the enzyme for catalysis, and the Vps15 regulatory subunit, which binds to this and the preceding helix, may facilitate this process. This C-terminal region may also represent a target for specific, non-ATP-competitive PtdIns3K inhibitors.

SUBMITTER: Miller S

PROVIDER: S-EPMC3321845 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Finding a fitting shoe for Cinderella: searching for an autophagy inhibitor.

Miller Simon S Oleksy Arkadiusz A Perisic Olga O Williams Roger L RL

Autophagy 20100803 6

Vps34 is the ancestral phosphatidylinositol 3-kinase (PtdIns3K) isoform and is essential for endosomal trafficking of proteins to the vacuole/lysosome, autophagy and phagocytosis. Vps34-containing complexes associate with specific cellular compartments to produce PtdIns(3)P. Understanding the roles of Vps34 has been hampered by the lack of potent, specific inhibitors. To boost development of Vps34 inhibitors, we determined the crystal structures of Vps34 alone and in complexes with multitargeted ...[more]

PMID: 20574157

Similar Datasets

Project description:BackgroundIll-fitting footwear is a common problem in older people. The objective of this study was to determine the accuracy of shoe fitting in older people by comparing the dimensions of allocated shoes to foot dimensions obtained with a three-dimensional (3D) scanner.MethodsThe shoe sizes of 56 older people were determined with the Brannock device®, and weightbearing foot scans were obtained with the FotoScan 3D scanner (Precision 3D Ltd, Weston-super-mare, UK). Participants were provided with a pair of shoes (Dr Comfort®, Vista, CA, USA), available in three width fittings (medium, wide and extra wide). The dimensions (length, ball width and ball girth) of the allocated shoes were documented according to the last measurements provided by the manufacturer. Mean differences between last dimensions and foot dimensions obtained with the 3D scanner were calculated to provide an indication of shoe fitting accuracy. Participants were also asked to report their perception of shoe fit and comfort, using 100 mm visual analogue scales (VAS).ResultsShoe size ranged from US size 7 to 14 for men and 5.5 to 11 for women. The allocated shoes were significantly longer than the foot (mean 23.6 mm, 95% confidence interval [CI] 22.1 to 25.2; t55?=?30.3, p?<?0.001), however there were no significant differences in relation to ball width (mean 1.4 mm, 95% CI -0.1 to 2.9 mm; t55?=?1.9, p?=?0.066) or ball girth (mean -0.7 mm, 95% CI -6.1 to 4.8 mm; t55?=?-0.2, p?=?0.810). Participants reported favourable perceptions of shoe fit (mean VAS?=?90.7 mm, 95% CI 88.4 to 93.1 mm) and comfort (mean VAS?=?88.4 mm, 95% CI 85.0 to 91.8 mm).ConclusionShoe size selection using the Brannock device® resulted in the allocation of shoes with last dimensions that were well matched to the dimensions of the foot. Participants also considered the shoes to be well fitted and comfortable. Older people with disabling foot pain can therefore be dispensed with appropriately-fitted shoes using this technique, provided that the style and materials used are suitable and extra width fittings are available.

Project description:BACKGROUND:Falls in older people are common and can result in loss of confidence, fear of falling, restriction in activity and loss of independence. Causes of falls are multi-factorial. There is a paucity of research assessing the footwear characteristics among older people who are at high risk of falls, internationally and in the Irish setting. The aim of this study was to examine the proportion of older adults attending a geriatric day hospital in Ireland who were wearing incorrectly sized shoes. METHODS:A consecutive sample of 111 older adults aged 60?years and over attending a geriatric day hospital in a large Irish teaching hospital was recruited. Demographic data including age, mobility, medications, co-habitation status, footwear worn at home and falls history were recorded. Shoe size and foot length were measured in millimetres using an internal shoe gauge and SATRA shoe size stick, respectively. Participants' self-reported shoe size was recorded. Footwear was assessed using the Footwear Assessment Form (FAF). A Timed Up and Go (TUG) score was recorded. Functional independence was assessed using the Nottingham Extended Activities of Daily Living (NEADL) Scale. The primary outcome of interest in this study was selected as having footwear within the suggested range (10 to 15?mm) on at least one foot. Participants who met this definition were compared to those with ill-fitting footwear on both feet using Chi-square tests, T-tests or Mann-Whitney U tests. RESULTS:The mean difference between shoe length and foot length was 18.6?mm (SD: 9.6?mm). Overall, 72% of participants were wearing footwear that did not fit correctly on both feet, 90% had shoes with smooth, partly worn or fully worn sole treading and 67% reported wearing slippers at home. Participant age, TUG score and NEADL score were not associated with ill-fitting footwear. CONCLUSIONS:Wearing incorrectly fitting shoes and shoes with unsafe features was common among older adults attending geriatric day services in this study. A large number of participants reported wearing slippers at home.

Dataset Information

Finding a fitting shoe for Cinderella: searching for an autophagy inhibitor.

Publications

Finding a fitting shoe for Cinderella: searching for an autophagy inhibitor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets