An alternative processing pathway of APP reveals two distinct cleavage modes for rhomboid protease RHBDL4.

Biological Chemistry
Sherilyn Junelle RecintoLisa Marie Munter

Abstract

Since the first genetic description of a rhomboid in Drosophila melanogaster, tremendous efforts have been geared towards elucidating the proteolytic mechanism of this particular class of intramembrane proteases. In particular, mammalian rhomboid proteases sparked our interest and we aimed to investigate the human homologue RHBDL4. In light of our recent finding of the amyloid precursor protein (APP) family as efficient substrates of RHBDL4, we were enticed to further study the specific proteolytic mechanism of this enzyme by comparing cleavage patterns of wild type APP and APP TMS chimeras. Here, we demonstrate that the introduction of positively charged amino acid residues in the TMS redirects the RHBDL4-mediated cleavage of APP from its ectodomain closer towards the TMS, possibly inducing an ER-associated degradation (ERAD) of the substrate. In addition, we concluded that the cytoplasmic tail and proposed palmitoylation sites in the ectodomain of APP are not essential for the RHBDL4-mediated APP processing. In summary, our previously identified APP ectodomain cleavages by RHBDL4 are a subsidiary mechanism to the proposed RHBDL4-mediated ERAD of substrates likely through a single cleavage near or within the TMS.

References

Oct 28, 2005·The EMBO Journal·Constanze ReinhardBart De Strooper
Oct 20, 2006·Nature·Yongcheng WangYa Ha
Jan 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·M Joanne LemieuxMichael N G James
Dec 27, 2007·Molecular Cell·Marius K Lemberg, Matthew Freeman
Aug 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Amina El AyadiDarren Boehning
Jul 5, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Raja BhattacharyyaDora M Kovacs
Jul 13, 2013·Biochimica Et Biophysica Acta·Lisa N Kinch, Nick V Grishin
Jul 1, 2014·TheScientificWorldJournal·Tsung-Lin ChengHua-Lin Wu
Jul 11, 2014·The EMBO Journal·Elena ArutyunovaM Joanne Lemieux
Jul 17, 2014·The EMBO Journal·Kvido Strisovsky, Matthew Freeman
Dec 31, 2015·The FEBS Journal·Kvido Strisovsky
Jul 6, 2016·Seminars in Cell & Developmental Biology·Marius K Lemberg, Colin Adrain
Aug 27, 2016·The Journal of Biological Chemistry·Sandra PaschkowskyLisa Marie Munter
Apr 1, 2017·Nature Reviews. Neuroscience·Ulrike C MüllerMartin Korte
Apr 15, 2017·European Biophysics Journal : EBJ·Martin B UlmschneiderStephen H White
Apr 28, 2017·Oncotarget·Fei MiaoLinfang Wang
Dec 21, 2017·The Journal of Membrane Biology·Sandra PaschkowskyLisa Marie Munter

❮ Previous
Next ❯

Citations

Jul 10, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Rachel R Kandel, Sonya E Neal

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.

Related Papers

Journal of Nutrition Education and Behavior
Karen Chapman-Novakofski
The Canadian Journal of Hospital Pharmacy
Douglas Sellinger
Psychotherapie, Psychosomatik, medizinische Psychologie
B Strauss, H Kächele
The Oncologist
Justin F Gainor
© 2022 Meta ULC. All rights reserved