Etiketter

onsdag 22 januari 2020

Metzinkiinisuperperhe, alaperhe Astasiinit: Alaryhmä Mepriinit , Mepriini beta

Meprin beta
https://www.ncbi.nlm.nih.gov/pubmed/31604820
2019 Nov 22;294(47):17768-17776. doi: 10.1074/jbc.RA119.008310. Epub 2019 Oct 11.

Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP695 numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), even though the total plasma membrane level of APP was unchanged compared with APP levels in cells expressing APPwt or APP-S675A. Moreover, the level of an alternative larger C-terminal fragment (CTF) increased in the APP-S675E cells, whereas the CTF form that was most abundant in cells expressing APPwt or APP-S675A decreased in the APP-S675E cells. Upon siRNA-mediated knockdown of the astacin metalloprotease meprin β, the levels of the alternative CTF decreased and the CTF ratio was restored back to APPwt levels. Our findings suggest that APP-Ser-675 phosphorylation alters the balance of APP processing, increasing meprin β-mediated and decreasing α-secretase-mediated processing of APP at the plasma membrane. As meprin β cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Aβ2-40/42 peptides, enhanced APP processing by this enzyme could contribute to AD pathology. We propose that it would be of interest to clarify in future studies how APP-Ser-675 phosphorylation promotes meprin β-mediated APP cleavage.

KEYWORDS:

ADAM; APP-CTF; Alzheimer's disease; amyloid precursor protein (APP); amyloid-beta (Aβ); meprin β; neurodegeneration; proteolytic processing; β-secretase 1 (BACE1)
PMID:
31604820
PMCID:
PMC6879340
DOI:
10.1074/jbc.RA119.008310


Tässä katson TRIM37, jolla on domeenit RBC ja MATH ( (Meprin and TRAF Homolog). Kor. 17  sijainti.
Mitenkähän tämä toimii normaalisti?  Se vaikuttaa radioreistenssiä, joka havaitaan  silloin kun kätyetään cisplatiinia tuumoriin..

https://www.ncbi.nlm.nih.gov/pubmed/30254148 
 Conserved Domains (4) summary
smart00502
Location:132254
BBC; B-Box C-terminal domain
cd00162
Location:1558
RING; RING-finger (Really Interesting New Gene) domain, a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc; defined by the 'cross-brace' motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)-(N/C/H)-X2-C-X(4-48)C-X2-C; probably involved in ...
cd03773
Location:273406
MATH_TRIM37; Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. ...https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=239742
 The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.
pfam00643
Location:90132
zf-B_box;

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