Presenilin-1 (PS-1) je presenilinski protein koji je kod ljudi kodiran genom PSEN1. Genski lokus PSEN1 nalazi se u telomernoj polovini dugog (q) kraka hromosoma 14.[5] Presenilin-1 je jedan od četiri jezgarna proteina u kompleksu gama sekretaza, za koji se smatra da ima važnu ulogu u stvaranju amiloida beta (Aβ) iz amiloidnog proteinskog prekursora (APP ). Akumulacija amiloida-beta povezana je s početkom Alzheimerove bolesti.[6]

PSEN1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

2KR6, 5A63, 4UIS, 5FN3, 5FN4, 5FN5, 5FN2

Identifikatori
AliasiPSEN1
Vanjski ID-jeviOMIM: 104311 MGI: 1202717 HomoloGene: 7186 GeneCards: PSEN1
Lokacija gena (čovjek)
Hromosom 14 (čovjek)
Hrom.Hromosom 14 (čovjek)[1]
Hromosom 14 (čovjek)
Genomska lokacija za PSEN1
Genomska lokacija za PSEN1
Bend14q24.2Početak73,136,418 bp[1]
Kraj73,223,691 bp[1]
Lokacija gena (miš)
Hromosom 12 (miš)
Hrom.Hromosom 12 (miš)[2]
Hromosom 12 (miš)
Genomska lokacija za PSEN1
Genomska lokacija za PSEN1
Bend12 D1|12 38.84 cMPočetak83,734,926 bp[2]
Kraj83,781,973 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija PDZ domain binding
cadherin binding
GO:0070122 peptidase activity
beta-catenin binding
GO:0001948, GO:0016582 protein binding
calcium channel activity
aspartic-type endopeptidase activity
endopeptidase activity
hydrolase activity
aspartic endopeptidase activity, intramembrane cleaving
Ćelijska komponenta Jedarna membrana
membrana
mitohondrija
ciliary rootlet
neuron projection
gamma-secretase complex
Jedro
Kinetohor
centrosom
rough endoplasmic reticulum
dendritic shaft
aggresome
cell surface
membrane-bounded organelle
Endoplazmatski retikulum
Lipidni splav
Golđijev aparat
growth cone
Nervno-mišićna veza
intracellular anatomical structure
Akson
nuclear outer membrane
endoplasmic reticulum membrane
Golđijeva membrana
integral component of plasma membrane
smooth endoplasmic reticulum
lysosomal membrane
međućelijske veze
dendrit
presynapse
mitochondrial inner membrane
GO:0016023 citoplazmatska vezikula
citoplazma
Ćelijska membrana
cell cortex
integral component of membrane
azurophil granule membrane
Z disc
neuronal cell body
perinuklearno područje citoplazme
early endosome
Sinapsna vezikula
GO:0009327 protein-containing complex
Sarkolema
sinapsa
synaptic membrane
integral component of presynaptic membrane
endozom
early endosome membrane
projekcija ćelije
Biološki proces GO:1904089 negative regulation of neuron apoptotic process
somitogenesis
positive regulation of protein phosphorylation
positive regulation of MAP kinase activity
GO:0048554 positive regulation of catalytic activity
mitochondrial transport
post-embryonic development
positive regulation of dendritic spine development
cellular response to DNA damage stimulus
heart looping
blood vessel development
membrane protein ectodomain proteolysis
regulation of epidermal growth factor-activated receptor activity
regulation of resting membrane potential
regulation of synaptic transmission, glutamatergic
amyloid precursor protein catabolic process
GO:0097285 Apoptoza
thymus development
positive regulation of coagulation
negative regulation of apoptotic signaling pathway
neuron development
Memorija
endoplasmic reticulum calcium ion homeostasis
GO:0001306 response to oxidative stress
autophagosome assembly
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
heart development
negative regulation of axonogenesis
embryonic limb morphogenesis
locomotion
learning or memory
protein transport
cerebral cortex cell migration
positive regulation of proteasomal ubiquitin-dependent protein catabolic process
L-glutamate transmembrane transport
brain morphogenesis
Notch signaling pathway
GO:0033128 negative regulation of protein phosphorylation
myeloid leukocyte differentiation
neuron apoptotic process
smooth endoplasmic reticulum calcium ion homeostasis
synaptic vesicle targeting
Cajal-Retzius cell differentiation
skin morphogenesis
negative regulation of protein kinase activity
cell fate specification
skeletal system morphogenesis
regulation of phosphorylation
cellular calcium ion homeostasis
epithelial cell proliferation
neuron migration
negative regulation of apoptotic process
GO:1901227 negative regulation of transcription by RNA polymerase II
Proteoliza
regulation of synaptic plasticity
negative regulation of epidermal growth factor-activated receptor activity
Ćelijska adhezija
hematopoietic progenitor cell differentiation
neuron differentiation
cerebral cortex development
canonical Wnt signaling pathway
dorsal/ventral neural tube patterning
neural retina development
positive regulation of protein kinase activity
T cell activation involved in immune response
neurogenesis
GO:0007243 intracellular signal transduction
protein processing
protein maturation
myeloid dendritic cell differentiation
Autofagija
GO:0033578, GO:0033577, GO:0033575, GO:0033576 protein glycosylation
brain development
negative regulation of ubiquitin-protein transferase activity
choline transport
positive regulation of apoptotic process
Notch receptor processing
negative regulation of ubiquitin-dependent protein catabolic process
forebrain development
regulation of protein binding
T cell receptor signaling pathway
segmentation
positive regulation of receptor recycling
calcium ion transmembrane transport
amyloid-beta formation
amyloid precursor protein metabolic process
neutrophil degranulation
regulation of canonical Wnt signaling pathway
amyloid-beta metabolic process
positive regulation of L-glutamate import across plasma membrane
astrocyte activation involved in immune response
regulation of neuron projection development
cerebellum development
positive regulation of protein binding
Notch receptor processing, ligand-dependent
positive regulation of phosphorylation
astrocyte activation
synapse organization
cell-cell adhesion
cellular response to amyloid-beta
negative regulation of core promoter binding
negative regulation of low-density lipoprotein receptor activity
positive regulation of amyloid fibril formation
neuron projection maintenance
membrane protein intracellular domain proteolysis
positive regulation of protein import into nucleus
ephrin receptor signaling pathway
GO:1901313 positive regulation of gene expression
negative regulation of gene expression
positive regulation of glycolytic process
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_000021
NM_007318
NM_007319

NM_008943
NM_001362271

RefSeq (bjelančevina)

NP_000012
NP_015557

NP_001349200

Lokacija (UCSC)Chr 14: 73.14 – 73.22 MbChr 12: 83.73 – 83.78 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Aminokiselinska sekvenca uredi

Dužina polipeptidnog lanca je 467 aminokiselina, a molekulska težina 52 668 Da.[7].

1020304050
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPL
SNGRPQGNSRQVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATI
KSVSFYTRKDGQLIYTPFTEDTETVGQRALHSILNAAIMISVIVVMTILL
VVLYKYRCYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYNVAVDYITVAL
LIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKYLPEWTAWLIL
AVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGP
HRSTPESRAAVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATA
SGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATD
YLVQPFMDQLAFHQFYI
Simboli

Struktura uredi

Presenilin ima topologiju transmembranskog domena 9, sa vanćelijskim C-krajem i citosolnim N-terminalom.[8][9] Presenilin se podvrgava endoproteolitskoj obradi za proizvodnju ~ 27-28 kDa N-terminalnih i ~16-17 kDa C-terminalnih fragmenata kod ljudi.[10] Nadalje, presenilin u ćelijama postoji uglavnom kao heterodimer fragmenata C– i N-kraja.[10] When presenilin 1 is overexpressed, the full length protein accumulates in an inactive form.[11] Based on evidence that a gamma-secretase inhibitor binds to the fragments,[12] the cleaved presenilin complex is considered to be the active form.[13]

Funkcija uredi

Pretpostavlja se da presenilini reguliraju obradu APP -a svojim djelovanjem na gama sekretazu, enzim koji cijepa APP. Također, smatra se da su presenilini uključeni u cijepanje zareznog receptora, tako da oni ili direktno reguliraju aktivnost gama sekretaza ili su sami enzimi proteaza. Za ovaj gen identificirano je više varijanti alternativno prerađenih transkripta, a samo neki imaju tvrđenu prirodu pune dužine.[14]

Korelacija genotipfenotip uredi

Da bi istražili utjecaj mutacije gena glu280-do-ala presenilin-1 na regijsku cerebralnu perfuziju, primijenjeno je SPECT skeniranje kod 57 osoba jednog velikog rodoslova s ranom pojavom Alzheimerove bolesti. Uzorak je uključivao 23 osobe koje nisu bili nositelji mutacije PS1 i bili su kognitivno normalni, 18 koji su bili asimptomski i 16 koji su bili nositelji mutacija sa kliničkom dijagnozom AD. Asimptomski ispitanici sa PS1 mutacijama pokazali su smanjenu perfuziju u poređenju sa normalnim kontrolnim ispitanicima u hipokampusnom kompleksu, prednjem i zadnjem cingulatu, zadnjem parijetalnom režnju i prednjem čeonom režnju. Pacijenti s AD -om pokazali su smanjenu perfuziju u stražnjem parijetalnom i gornjem frontalnom korteksu u usporedbi s normalnim kontrolnim osobama. Ovaj metod diskriminirao je 86% ispitanika u tri grupe (p < 0,0005). Zaključeno je su da su regionalne abnormalnosti cerebralne perfuzije na osnovu SPECT-a uočljive prije razvoja kliničkih simptoma Alzheimerove bolesti kod nositelja mutacije glu280-ala PS1.

Analizom genotipa velikog kolumbijskog rodoslovba sa 109 nositela mutacije E280A PS1, uključujući 52 člana sa AD, otkrivemno je da je vjerovatnije da će osobe s najmanje jednim alelom APOE4 razviti AD u ranijoj dobi od onih bez alela APOE4, što ukazuje na epistatski efekt. Varijante promotora APOE nisu uticale ni na početak ni na trajanje bolesti.

Evolucija uredi

Paralozi presenilinskih homologa vrlo sličnih sekvenci poznati su kod biljaka, beskičmenjaka i kičmenjaka. Pretragom različitih baza podataka mogu se identificirati porodice proteina homolognih presenilinima. Članovi ove porodice, homolozi presenilina, imaju značajne sličnosti u sekvenci sa presenilinima i također imaju po dva konzervirana ostatka aspartatske kiseline u susjednim predviđenim transmembranskim segmentima. Porodica presenilin homologa pronađena je širom eukariota, gljiva, u biljkama i životinjama, te u arhejama. U ljudskom genomu otkriveno je pet homologa presenilina, od kojih tri posjeduju domene povezane s proteazom, koje su u skladu s predloženom funkcijom presenilinskih proteaza. Na osnovu ovih nalaza, predloženo je da presenilini i njegovi homolozi predstavljaju različite podgrane veće porodice astopilnih proteaza povezanih s politopskom membranom.

Klinički značaj uredi

Proizvodnja beta-amiloida uredi

Transgeni miševi koji prekomjerno eksprimiraju mutantni presenilin-1 pokazuju porast beta-amiloid-42 (43) u mozgu, što sugerira da presenilin-1 ima važnu ulogu u regulaciji beta-amiloida i može biti u velikoj vezi sa Alzheimerovom bolešću.[15] Daljnje istraživanje provedeno u kulturama neurona mišjeg embriona s nedostatkom presenilina-1. Pokazali su da je cijepanje alfa– i beta-sekretazom još uvijek normalno bez prisustva presenilina-1. U međuvremenu je ukinuto cijepanje gama-cijepanjem transmembranskog domena APP. Primijećen je petostruki pad razine amiloidnog peptida, što sugerira da nedostatak presenilina-1 može podregulirati amiloid, a inhibicija presenilina-1 može biti potencijalni metod za anti-amiloidogenu terapiju kod Alzheimerove bolesti.[16] Opsežno istraživanje o ulozi presenilina-1 u proizvodnji amiloida provedeno je kako bi se poboljšalo bolje razumijevanje Alzheimerove bolesti.[17][18]

Alzheimerova bolest uredi

Pacijenti sa nasljednim oblikom Alzheimerove bolesti (AD) mogu imati mutacije u proteinima presenilina (PSEN1; PSEN2) ili proteinima amiloidnog prekursora (APP). Ove mutacije povezane s bolešću rezultiraju povećanom proizvodnjom dužeg oblika amiloida beta (glavne komponente amiloidnih naslaga pronađenih u mozgu bolesnika sa AD). Ove mutacije rezultiraju ranom pojavom Alzheimerove bolesti, koja je rijedak oblik ove bolesti. Ove rijetke genetičke varijante su autosomno dominantne.[19]

Kancer uredi

Pored uloge u Alzheimerovoj bolesti, presenilin-1 je također važan i za rak. Provedeno je istraživanje ekspresije gena širokog raspona na ljudskom malignom melanomu. Istraživači su klasifikovali ćelijske linije malignog melanoma u dva tipa. Studija je pokazala da je presenilin-1 podreguliran kod ćelijskog tipa, dok je preeksprimiran kod drugog tipa ćelija.[20]

Drugo istraživanje o ćelijskoj liniji otpornosti na više lijekova (MDR) također otkriva ulogu presenilina-1 u razvoju raka. Zbog razvoja otpornosti na hemikalije, MDR ćelije postaju kritični faktor uspjeha hemoterapija raka.[21] U studiji su istraživači pokušali pronaći molekulski mehanizam, istražujući ekspresiju unutarćelijskog domena Notch1 (N1IC) i presenilin 1. Otkrili su da postoji ekspresija oba nivoa na višem nivou i da je protein 1 povezan s rezistencijom na više lijekova (ABCC1); utvrđeno je i da je reguliran N1IC, koji sugerira mehanizam ABCC1 reguliran presenilinom 1 i zareznom signalizacijom.[22]

Interakcije uredi

Pokazano je da PSEN1 ima interakcije sa:

Reference uredi

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