Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and γ-secretase activity

Presenilin 1 (PS1) interacts with telencephalin (TLN) and the amyloid precursor protein via their transmembrane domain (Annaert, W.G., C. Esselens, V. Baert, C. Boeve, G. Snellings, P. Cupers, K. Craessaerts, and B. De Strooper. 2001. Neuron. 32:579–589). Here, we demonstrate that TLN is not a substrate for γ-secretase cleavage, but displays a prolonged half-life in PS1−/− hippocampal neurons. TLN accumulates in intracellular structures bearing characteristics of autophagic vacuoles including the presence of Apg12p and LC3. Importantly, the TLN accumulations are suppressed by adenoviral expression of wild-type, FAD-linked and D257A mutant PS1, indicating that this phenotype is independent from γ-secretase activity. Cathepsin D deficiency also results in the localization of TLN to autophagic vacuoles. TLN mediates the uptake of microbeads concomitant with actin and PIP2 recruitment, indicating a phagocytic origin of TLN accumulations. Absence of endosomal/lysosomal proteins suggests that the TLN-positive vacuoles fail to fuse with endosomes/lysosomes, preventing their acidification and further degradation. Collectively, PS1 deficiency affects in a γ-secretase–independent fashion the turnover of TLN through autophagic vacuoles, most likely by an impaired capability to fuse with lysosomes.

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The Extreme C Terminus of Presenilin 1 Is Essential for γ-Secretase Complex Assembly and Activity

Journal of Biological Chemistry ◽

10.1074/jbc.m407717200 ◽

2004 ◽

Vol 279 (44) ◽

pp. 45564-45572 ◽

Cited By ~ 35

Author(s):

Anna Bergman ◽

Hanna Laudon ◽

Bengt Winblad ◽

Johan Lundkvist ◽

Jan Näslund

Keyword(s):

Transmembrane Domain ◽

Amyloid Β ◽

Presenilin 1 ◽

Amyloid Β Peptide ◽

Terminal Part ◽

Complex Assembly ◽

Terminal Fragment ◽

C Terminus ◽

Secretase Activity ◽

Endoproteolytic Cleavage

The γ-secretase complex catalyzes the cleavage of the amyloid precursor protein in its transmembrane domain resulting in the formation of the amyloid β-peptide and the cytoplasmic APP intracellular domain. The active γ-secretase complex is composed of at least four subunits: presenilin (PS), nicastrin, Aph-1, and Pen-2, where the presence of all components is critically required for γ-cleavage to occur. The PS proteins are themselves subjected to endoproteolytic cleavage resulting in the generation of an N-terminal and a C-terminal fragment that remain stably associated as a heterodimer. Here we investigated the effects of modifications on the C terminus of PS1 on PS1 endoproteolysis, γ-secretase complex assembly, and activity in cells devoid of endogenous PS. We report that certain mutations and, in particular, deletions of the PS1 C terminus decrease γ-secretase activity, PS1 endoproteolysis, and γ-secretase complex formation. We demonstrate that the N- and C-terminal PS1 fragments can associate with each other in mutants having C-terminal truncations that cause loss of interaction with nicastrin and Aph-1. In addition, we show that the C-terminal fragment of PS1 alone can mediate interaction with nicastrin and Aph-1 in PS null cells expressing only the C-terminal fragment of PS1. Taken together, these data suggest that the PS1 N- and C-terminal fragment intermolecular interactions are independent of an association with nicastrin and Aph-1, and that nicastrin and Aph-1 interact with the C-terminal part of PS1 in the absence of an association with full-length PS1 or the N-terminal fragment.

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Faculty Opinions recommendation of Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1003481.200009 ◽

2003 ◽

Author(s):

Raphael Kopan

Keyword(s):

Presenilin 1 ◽

Gamma Secretase ◽

Secretase Activity

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P1-169: Transmembrane domain of CRB2 is indispensable for inhibition of γ-secretase activity

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.04.175 ◽

2009 ◽

Vol 5 (4S_Part_8) ◽

pp. P226-P227

Author(s):

Masaki Nishimura ◽

Yachiyo Mitsuishi ◽

Hiroshi Hasegawa ◽

Akinori Matsuo ◽

Shinji Tagami ◽

...

Keyword(s):

Transmembrane Domain ◽

Secretase Activity

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Conformation of the transmembrane domains in peripheral myelin protein 22. Part 1. Solution-phase synthesis and circular dichroism study of protected 17-residue partial peptides in the first putative transmembrane domain*

Journal of Peptide Research ◽

10.1034/j.1399-3011.2003.00073.x ◽

2003 ◽

Vol 62 (2) ◽

pp. 78-87 ◽

Cited By ~ 4

Author(s):

K. Yamada ◽

J. Sato ◽

H. Oku ◽

R. Katakai

Keyword(s):

Transmembrane Domain ◽

Transmembrane Domains ◽

Solution Phase ◽

Myelin Protein ◽

Phase Synthesis ◽

Peripheral Myelin Protein 22 ◽

Peripheral Myelin Protein ◽

Putative Transmembrane Domain ◽

Solution Phase Synthesis ◽

Circular Dichroïsm

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Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production

Journal of Neurochemistry ◽

10.1111/jnc.12996 ◽

2015 ◽

Vol 133 (3) ◽

pp. 409-421 ◽

Cited By ~ 9

Author(s):

Alexandre Matz ◽

Blanka Halamoda-Kenzaoui ◽

Romain Hamelin ◽

Sebastien Mosser ◽

Jean-René Alattia ◽

...

Keyword(s):

Presenilin 1 ◽

Secretase Activity ◽

Aβ Production

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Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1

The EMBO Journal ◽

10.1038/emboj.2011.372 ◽

2011 ◽

Vol 30 (23) ◽

pp. 4815-4824 ◽

Cited By ~ 85

Author(s):

Yu Ohki ◽

Takuya Higo ◽

Kengo Uemura ◽

Naoaki Shimada ◽

Satoko Osawa ◽

...

Keyword(s):

Transmembrane Domain ◽

Presenilin 1

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The 2A proteins of three diverse picornaviruses are related to each other and to the H-rev107 family of proteins involved in the control of cell proliferation

Microbiology ◽

10.1099/0022-1317-81-1-201 ◽

2000 ◽

Vol 81 (1) ◽

pp. 201-207 ◽

Cited By ~ 110

Author(s):

Pamela J. Hughes ◽

Glyn Stanway

Keyword(s):

Transmembrane Domain ◽

Genome Structure ◽

Protein Processing ◽

Cellular Proteins ◽

Structural Proteins ◽

Aichi Virus ◽

Macromolecular Synthesis ◽

Putative Transmembrane Domain ◽

Encephalomyelitis Virus ◽

Processing Event

The 2A protein appears to be diverse among picornaviruses, in contrast to the other non-structural proteins, which have homologous structures and functions. In enteroviruses and rhinoviruses, 2A is a trypsin-like protease involved in protein processing and in shut-off of host-cell macromolecular synthesis. The aphthovirus and cardiovirus 2A is associated with an unusual processing event at the 2A/2B junction. It is shown here that the 2A protein of several diverse picornaviruses, the human parechoviruses, Aichi virus and avian encephalomyelitis virus, possess previously unrecognized conserved motifs and are likely to have a common function. Moreover, these motifs, a conserved histidine and flanking amino acids, an asparagine–cysteine dipeptide and a putative transmembrane domain, are characteristic of a family of cellular proteins, at least two of which are involved in the control of cell growth. These observations have important implications for an understanding of picornavirus genome structure and evolution, as well as pointing to possible functions of 2A in these viruses.

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