gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site
Authors: Wenjuan Ye
Michael S Wolfe
Patrick C Fraering
Beth L Ostaszewski
Dennis J Selkoe
Matthew J LaVoie
Journal: Journal of Biological Chemistry (2005)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: gamma-Secretase; protease; intramembrane; catalytic site; cleaves
Affiliations: Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract:  gamma-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of gamma-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified gamma-secretase to selectively block cleavage of APP- but not Notch-based substrates. Moreover, ATP activated the generation of the APP intracellular domain and Abeta, but not the generation of the Notch intracellular domain by the purified protease complex, and was a direct competitor of the APP-selective inhibitors, as were other nucleotides. In accord, purified gamma-secretase bound specifically to an ATP-linked resin. Finally, a photoactivable ATP analog specifically labeled presenilin 1-C-terminal fragments in purified gamma-secretase preparations; the labeling was blocked by ATP itself and APP-selective gamma-secretase inhibitors. We concluded that a nucleotide-binding site exists within gamma-secretase, and certain compounds that bind to this site can specifically modulate the generation of Abeta while sparing Notch. Drugs targeting the gamma-secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease. 

Retracted: No

PubPeer comments:
 Fig 1  C, PKMYT1 levels in OC tissues and adjacent normal tissues. D, PKMYT1 levels in OC patients either with distant metastasis or not . In 1C, the distribution of PKMYT1 levels in OC tissues range from 6.5 to 17.5. When the tissues are grouped into distant-metastatic and non-metastatic groups in 1D, the PKMYT1 levels range from 2 to 16. Am I missing something?  , 
 Figs 1B, 3D.  Survival in OC patients expressing high or low level of PKMYT1 ...  Survival in OC patients expressing high or low level of SIRT3. The two pairs of K-M curves do not appear to be compatible. There are deaths in one pair with no corresponding death in the other.  , 
 This paper appears to be part of a set of papers (n=175 as of today and growing) that share a very similar layout. Subsets of these papers appear to share similar Kaplan-Meier survival plots, correlation plots, and overlapping photos of wound-healing, transwell assays, etc. Yet, there is little to no overlap between the authors of these papers or their departments and affiliated institutions. The very similar layout and overlapping photos suggest these papers might have all been created by the same entity, perhaps a paper mill. I have been calling this set the  Comb papers, because the Kaplan-Meier plots have a comb-like appearance. For PubPeer user Hoya Camphorifolia, the survival plots look like Lego blocks. This particular paper is part of a subset of at least two papers within the Comb papers that share very similar correlation plots: * ZH Xuan et al., ERMPS (2020), DOI: 10.26355 eurrev_202005_21308 - https: pubpeer.com publications D3FC467A77D84555D4E32E7908A0A9 * ZG Shen et al., ERMPS (2020), DOI: 10.26355 eurrev_202005_21164 - https: pubpeer.com publications FA13397A001FA8940B51F74F192D76  ,