Positive Evolutionary Selection of an HD Motif on Alzheimer Precursor Protein Orthologues Suggests a Functional Role

HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Aβ) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Aβ HD is part of a presumed, RGD-like integrin-binding motif RHD; however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modeling that the presence of HD on CAEDs cannot be the result of neutral evolutionary forces (p<0.0001). The motif is positively selected along the evolutionary process in the majority of APPOs, despite the fact that HD motif is underrepresented in the proteomes of all species of the animal kingdom. Position migration can be explained by high probability occurrence of multiple copies of HD on intermediate sequences, from which only one is kept by selective evolutionary forces, in a similar way as in the case of the “transcription binding site turnover.” CAED of all APP orthologues and homologues are predicted to bind metal ions including Amyloid-like protein 1 (APLP1) and Amyloid-like protein 2 (APLP2). Our results suggest that HDs on the CAEDs are most probably key components of metal-binding domains, which facilitate and/or regulate inter- or intra-molecular interactions in a metal ion-dependent or metal ion concentration-dependent manner. The involvement of naturally occurring mutations of HD (Tottori (D7N) and English (H6R) mutations) in early onset Alzheimer's disease gives additional support to our finding that HD has an evolutionary preserved function on APPOs

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

First known satellite collaring of a viverrid species: preliminary performance and implications of GPS tracking Malay civets (Viverra tangalunga)

The application of advanced technologies to the study of little-known species is a necessary step in generating effective conservation strategies. Despite the biological importance of the small carnivore guild, a paucity of data exists in terms of the spatial ecology of these species, largely due to logistical constraints of large and bulky collar units. This study reports the first known satellite collaring of a viverrid, the Malay civet (Viverra tangalunga), in Sabah, Malaysian Borneo. Stationary tests of two generations of 65–70 g e-obs GmbH ‘Collar 1A’ units recorded high fix success rates and good accuracy and precision under semi-open canopy. From October 2013–August 2015, nine adult V. tangalunga were fit with e-obs collars recording hourly nocturnal GPS locations. Collars were successfully deployed for 27–187 days. Field GPS fix success varied from 22 to 88.3 %, with the study documenting a total GPS success of 58.1 % across all individuals. Despite this large in-field performance range, the quality and quantity of data collected by these units surpass that of previous VHF studies on Asian viverrids, collecting on average a 16-fold increase in locations per collaring day. The successful application of satellite technology to these little-known carnivores carries significant biological and conservation implications, and it is recommended that satellite collars are a viable technology to conduct detailed and well-designed ecological studies of Viverridae species