Cleave but not leave: Astrotactin proteins in development and disease

Abstract

Over the years, animal studies have identified astrotactins as important membrane proteins for glial-guided neuronal migration during central nervous system development and hair follicle polarity control during skin development. Biochemical studies have revealed intramembrane proteolysis as an important feature of astrotactins. The two fragments of astrotactins remain linked together by a disulfide bond after the proteolytic cleavage. In humans, mutations in astrotactin genes have also been linked to a wide range of diseases, including several developmental brain disorders, neurodegenerative diseases and cancer. In this review, I will summarize the current knowledge of the biological function of astrotactins in development, highlight the linkage between mutations in astrotactin genes and human disease and discuss several outstanding questions that remain unanswered. © 2017 IUBMB Life, 69(8):572-577, 2017.

A Case Study on the Keap1 Interaction with Peptide Sequence Epitopes Selected by the Peptidomic mRNA Display

“…Although the structure of part of ASTN2, an isoform of ASTN1, was solved recently, the entire structure of ASTN1 is as‐yet unknown. However, two transmembrane domains have been predicted through their hydropathy profiles . According to the predicted topology, the most abundant peptide, Kc1, originating from ASTN1(475–485) is located in the extracellular domain.…”

“…Although the above formidable technical issue has hindered us from explicitly showing the direct PPI of Keap1 and ASTN1, the Astp1 sequence is known to be embedded in the extracellular domain of ASTN1, whereas Keap1 is localized in the cytosol. Thus, it seems unlikely that ASTN1 and Keap1 directly interact with each other under normal physiological conditions.…”

“…However, it has been reported that some proteins have transcript variants with different cellular localizations from that of the major transcript, for example, recent studies showed that the Wilms tumor suppressor protein (WTX), also known to interact with Keap1, is localized to the plasma membrane, whereas its shorter isoform, which lacks the N‐terminal phosphatidylinositol 4,5‐biphosphate binding domain, does not . It is known that there are several cleaved variants of ASTN1 produced by proteolysis, but, as far as we know, there have been no reports that the domain including the selected peptide sequence in this study localizes to the cytosol. If there is an unknown ASTN1 transcript variant(s) including the Astp1 sequence or its related sequences that localizes in the cytosol, our studies suggest that the variant may interact with Keap1 fairly selectively and strongly.…”

Profiles of gene expression in the hippocampal formation of rats with experimentally‐induced brain dysplasia

“…These include perturbation due to persistently increased Nr2f2 signaling, which in normal development promotes gliogenesis and blood–brain barrier specialization, but is normally developmentally constrained (Alvarez et al, ; Naka et al, ), thus raising the question of the consequences of ectopic or prolonged activation; loss of glial function related directly to peroxidation of membrane proteins by Cybb ; or altered communication with neurons. For instance, while the in vivo function of Astn2 is unknown, it shares homology with astrotactin ( Astn1 ), which is a well‐known neuronal protein responsible for neuron‐glia adhesion and glia‐mediated migration of neural precursors (Chang, ). Careful examination of these pathways could potentially allow us to narrow down the cellular populations involved, as well as the interrelation, causal or otherwise, of these factors.…”

Murine astrotactins 1 and 2 have similar membrane topology and mature via endoproteolytic cleavage catalyzed by signal peptidase

“…A recent structure of the C-terminal endodomain of Astn2 shows distinctive features responsible for its activity (9). Astn1 and Astn2 are believed to share the same membrane topology, with a cleaved Nterminal signal peptide (SP), two transmembrane helices (TMHs), and a large extracellular Cterminal domain (10). Both Astn1 and Astn2 undergo an endoproteolytic maturation step in which an unknown protease cleaves the protein just after the second TM segment, with the two fragments remaining attached through a single disulfide bond (10,11).…”