presenilins

presenilin 1; (Alzheimer's disease 3)
Identifiers
Symbol	PSEN1
Alt. symbols	AD3
Entrez	5663
HUGO	9508
OMIM	104311
RefSeq	NM_000021
UniProt	P49768
Other data
EC number	3.4.23.-
Locus	Chr. 14 q24.3

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Presenilin
	Solution structure of the human presenilin-1 CTF subunit.
Identifiers
Symbol	Presenilin
Pfam	PF01080
Pfam clan	CL0130
InterPro	IPR001108
MEROPS	A22
TCDB	1.A.54
OPM superfamily	277
OPM protein	4hyg
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/21 16:21:36」(JST)

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presenilin 2 (Alzheimer's disease 4)
Identifiers
Symbol	PSEN2
Alt. symbols	AD4
Entrez	5664
HUGO	9509
OMIM	600759
RefSeq	NM_000447
UniProt	P49810
Other data
EC number	3.4.23.-
Locus	Chr. 1 q31-q42

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge.^[3] Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.^[4]

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein.^[1] Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca²⁺ involved in presynaptic neurotransmitter release and long-term potentiation induction.^[5]

StructureEdit

The structure of presenilin-1 is still controversial, although recent research has produced a more widely accepted model. When first discovered, the PSEN1 gene was subjected to hydrophobicity analysis that predicted that the protein would contain ten trans-membrane domains. All previous models agreed that the first six putative membrane-spanning regions cross the membrane. These regions correspond to the N-terminal fragment of PS-1 but the structure of the C-terminal fragment was disputed. A recent paper by Spasic et al.^[6] provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. However, because this is a protein with large numbers of hydrophobic regions, it is unlikely that x-ray crystallography will provide definitive proof of the structure.

The structure of the presenilin-1 C-terminal catalytic fragment was determined using solution NMR. It is made up of alpha helices and is 176 amino acids in length.^[1] It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2). This information was found at the protein data bank

FunctionEdit

Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta (Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.

Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant.^[7] This can come about by various effects of the mutations upon gamma secretase.^[8] Presenilins are also implicated in the processing of notch, an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.^[9]

The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.^[3]

The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation.^[5] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca²⁺ release.^[5] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration".^[5]

ReferencesEdit

^ ^a ^b ^c Sobhanifar, S; Schneider, B; Löhr, F; Gottstein, D; Ikeya, T; Mlynarczyk, K; Pulawski, W; Ghoshdastider, U; Kolinski, M; Filipek, S; Güntert, P; Bernhard, F; Dötsch, V (2010). "Structural investigation of the C-terminal catalytic fragment of presenilin 1". Proceedings of the National Academy of Sciences 107 (21): 9644–9. doi:10.1073/pnas.1000778107. PMC 2906861. PMID 20445084.
^ PDB: 2KR6; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". To be published. doi:10.2210/pdb2kr6/pdb.
^ ^a ^b Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature 375 (6534): 754–60. doi:10.1038/375754a0. PMID 7596406.
^ Smialowska A, Baumeister R (2006). "Presenilin function in Caenorhabditis elegans". Neurodegener Dis 3 (4–5): 227–32. doi:10.1159/000095260. PMID 17047361.
^ ^a ^b ^c ^d Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (July 2009). "Presenilins are Essential for Regulating Neurotransmitter Release". Nature 460 (7255): 632–6. doi:10.1038/nature08177. PMC 2744588. PMID 19641596.
^ Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W (September 2006). "Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway". J. Biol. Chem. 281 (36): 26569–77. doi:10.1074/jbc.M600592200. PMID 16846981.
^ Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (January 1997). "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice". Nat. Med. 3 (1): 67–72. doi:10.1038/nm0197-67. PMID 8986743.
^ Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B (February 2006). "Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms". J. Neurochem. 96 (3): 732–42. doi:10.1111/j.1471-4159.2005.03578.x. PMID 16405513.
^ Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (May 1997). "Skeletal and CNS defects in Presenilin-1-deficient mice". Cell 89 (4): 629–39. doi:10.1016/S0092-8674(00)80244-5. PMID 9160754.

External linksEdit

The MEROPS online database for peptidases and their inhibitors: Presenilin 1 A22.001, Presenilin 2 A22.002
Dominantly Inherited Alzheimer Network (DIAN)
Dominantly Inherited Alzheimer Network (DIAN) Expanded Registry
Presenilins at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. アミロイド疾患の遺伝的要因 genetic factors in the amyloid diseases
2. 拡張型心筋症の遺伝学 genetics of dilated cardiomyopathy

English Journal

A ubiquitin-binding CUE domain in presenilin-1 enables interaction with K63-linked polyubiquitin chains.

Duggan SP1, Yan R1, McCarthy JV2.
FEBS letters.FEBS Lett.2015 Apr 13;589(9):1001-8. doi: 10.1016/j.febslet.2015.03.008. Epub 2015 Mar 18.
The presenilins (PS1 and PS2) are the catalytic component of the γ-secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including amyloid precursor protein (APP) and Notch. Herein, we describe the identification and
PMID 25796185

Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the γ-secretase complex.

Marinangeli C1, Tasiaux B1, Opsomer R1, Hage S2, Sodero AO1, Dewachter I1, Octave JN1, Smith SO3, Constantinescu SN4, Kienlen-Campard P5.
The Journal of biological chemistry.J Biol Chem.2015 Mar 13;290(11):7169-84. doi: 10.1074/jbc.M114.601286. Epub 2015 Jan 22.
Understanding the molecular mechanisms controlling the physiological and pathological activity of γ-secretase represents a challenging task in Alzheimer disease research. The assembly and proteolytic activity of this enzyme require the correct interaction of the 19 transmembrane domains (TMDs) pres
PMID 25614624

Presenilin-like GxGD membrane proteases have dual roles as proteolytic enzymes and ion channels.

Kuo IY1, Hu J1, Ha Y1, Ehrlich BE2.
The Journal of biological chemistry.J Biol Chem.2015 Mar 6;290(10):6419-27. doi: 10.1074/jbc.M114.629584. Epub 2015 Jan 21.
The GxGD proteases function to cleave protein substrates within the membrane. As these proteases contain multiple transmembrane domains typical of ion channels, we examined if GxGD proteases also function as ion channels. We tested the putative dual function by examining two archeobacterial GxGD pro
PMID 25609250

Japanese Journal

Modeling familial Alzheimer's disease with induced pluripotent stem cells

臨床神経学 52(11), 1134-1136, 2012
NAID 130004505083

家族性アルツハイマー病の病因遺伝子プレセニリン (アルツハイマー病--基礎研究から予防・治療の新しいパラダイム) -- (アルツハイマー病の病理・病態)

日本臨床 66(-), 144-149, 2008-01
NAID 40015816065

プレセニリン:ツメガエル分子発生学に基づく活性制御モデル

京都府立医科大学雑誌 116(11), 809-825, 2006-11
NAID 110004819855

Related Pictures

[doetsch-1] Sobhanifar, S; Schneider, B; Löhr, F; Gottstein, D; Ikeya, T; Mlynarczyk, K; Pulawski, W; Ghoshdastider, U; Kolinski, M; Filipek, S; Güntert, P; Bernhard, F; Dötsch, V (2010). "Structural investigation of the C-terminal catalytic fragment of presenilin 1". Proceedings of the National Academy of Sciences 107 (21): 9644–9. doi:10.1073/pnas.1000778107. PMC 2906861. PMID 20445084.

[Doetsch_2010-2] PDB: 2KR6; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". To be published. doi:10.2210/pdb2kr6/pdb.

[pmid7596406-3] Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature 375 (6534): 754–60. doi:10.1038/375754a0. PMID 7596406.

[pmid17047361-4] Smialowska A, Baumeister R (2006). "Presenilin function in Caenorhabditis elegans". Neurodegener Dis 3 (4–5): 227–32. doi:10.1159/000095260. PMID 17047361.

[Zhang-5] Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (July 2009). "Presenilins are Essential for Regulating Neurotransmitter Release". Nature 460 (7255): 632–6. doi:10.1038/nature08177. PMC 2744588. PMID 19641596.

[pmid16846981-6] Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W (September 2006). "Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway". J. Biol. Chem. 281 (36): 26569–77. doi:10.1074/jbc.M600592200. PMID 16846981.

[pmid8986743-7] Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (January 1997). "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice". Nat. Med. 3 (1): 67–72. doi:10.1038/nm0197-67. PMID 8986743.

[pmid16405513-8] Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B (February 2006). "Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms". J. Neurochem. 96 (3): 732–42. doi:10.1111/j.1471-4159.2005.03578.x. PMID 16405513.

[pmid9160754-9] Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (May 1997). "Skeletal and CNS defects in Presenilin-1-deficient mice". Cell 89 (4): 629–39. doi:10.1016/S0092-8674(00)80244-5. PMID 9160754.

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