Background: Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule.
Results: Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage site close to its GPI membrane linker domain. When we overexpressed BACE1 in CHO cells stably transfected with human contactin-2, we found increased release of soluble contactin-2 in the conditioned media. Conversely, pharmacological inhibition of BACE1 in CHO cells expressing human contactin-2 and mouse primary neurons decreased soluble contactin-2 secretion. The BACE1 cleavage site mutation 1008MM/AA dramatically impaired soluble contactin-2 release. We then asked whether contactin-2 release induced by BACE1 expression would concomitantly decrease cell surface levels of contactin-2. Using immunofluorescence and surface-biotinylation assays, we showed that BACE1 activity tightly regulates contactin-2 surface levels in CHO cells as well as in mouse primary neurons. Finally, contactin-2 levels were decreased in Alzheimer's disease brain samples correlating inversely with elevated BACE1 levels in the same samples.
Conclusion: Our results clearly demonstrate that mouse and human contactin-2 are physiological substrates for BACE1. BACE1-mediated contactin-2 cleavage tightly regulates the surface expression of contactin-2 in neuronal cells. Given the role of contactin-2 in cell adhesion, neurite outgrowth and axon guidance, our data suggest that BACE1 may play an important role in these physiological processes by regulating contactin-2 surface levels.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899608 | PMC |
| http://dx.doi.org/10.1186/1750-1326-9-4 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
TAG-1 Regulates NRP1 in Schwann Cells and Participates in Regulating Nerve Regeneration in Rats with Sciatic Nerve Crush Injury.
Neurochem Res
December 2024
Department of Spinal Surgery, Yantai Hospital of Traditional Chinese Medicine, No.39, Xingfu Road, Zhifu District, Yantai, 264000, China.
Schwann cells (SCs) are necessary for peripheral nerve regeneration due to their plasticity and trophic supply after sciatic nerve injury (SNI). However, the multiple adaptations of SCs are still poorly understood. This study explored the effects of transient axonal glycoprotein type-1 (TAG-1) on cell migration and neuropilin1 (NRP1) expression in SCs and examined the impact of TAG-1 on nerve regeneration in rats with SNI.
View Article and Find Full Text PDFCryo-EM structures of the full-length human contactin-2.
FEBS J
December 2024
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China.
Contactin-2 (CNTN2), an immunoglobulin cell adhesion molecule (IgCAM) expressed on the neural cell surface, regulates the formation of myelin sheaths, facilitates communication between neurons and axoglial cells, and coordinates the migration of neural cells. However, the assembly of full-length CNTN2 is still not fully elucidated. Here, we found that the full-length human CNTN2 forms a concentration-dependent homodimer.
View Article and Find Full Text PDFNovel genomic variants influencing methotrexate delayed clearance in pediatric patients with acute lymphoblastic leukemia.
Front Pharmacol
November 2024
Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Article Synopsis
- Methotrexate (MTX) is the main treatment for pediatric acute lymphoblastic leukemia (ALL), but some patients experience delayed clearance of high-dose MTX, leading to severe side effects.
- Whole-exome sequencing was conducted on 51 Korean pediatric ALL patients, analyzing 341 HD-MTX infusion data points to find genetic variants linked to delayed MTX clearance.
- Two specific genetic variants, rs1800956 and rs16954698, were identified as significantly associated with this delayed clearance, offering potential pathways to reduce toxic side effects through tailored treatments.
FUT8 Regulates Cerebellar Neurogenesis and Development Through Maintaining the Level of Neural Cell Adhesion Molecule Cntn2.
Mol Neurobiol
November 2024
The Children's Hospital, School of Medicine, National Clinical Research Center for Child Health, Zhejiang University, Hangzhou, 310052, China.
Core fucosylation at N-glycans, which is uniquely catalyzed by fucosyltransferase FUT8, plays essential roles in post-translational regulation of protein function. Aberrant core fucosylation leads to neurological disorders in individuals with congenital glycosylation disorders (CDG). However, the underlying mechanisms for these neurological defects remain largely unknown.
View Article and Find Full Text PDFFirst contact(in): The complete structure of contactin 2.
Structure
October 2024
Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands. Electronic address:
In this issue of Structure, Fan et al. report the structure of the full contactin 2 ectodomain, representing the first for the contactin family. The work reveals six immunoglobulin domains are essential for intercellular interactions, explores differences in proposed contactin 2 homodimerization mechanisms, and provides an updated model for contactin 2 organization on and between cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!