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Bioinformacijska analiza zunajcelične domene ADAM17 in priprava zapisov za njene skrajšane oblike
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BRATINA, ALJAŽ
(
Author
),
ID
Lenarčič, Brigita
(
Mentor
)
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Abstract
ADAM17 je transmembranska metaloproteaza, ki sodeluje v mnogih fizioloških in patoloških procesih. Katalizira odcep ektodomene nekaterih drugih transmembranskih proteinov, kar je ponavadi začetna stopnja v regulirani intramembranski proteolizi. S tem posredno sodeluje pri celičnem signaliziranju. Poleg tega se lahko veže na integrin α5β1 in tako omogoča interakcije med celicami. Zunajcelična domena ADAM17 je v zreli obliki sestavljena iz katalitične, disintegrinske in obmembranske domene ter kratke C-končne regije CANDIS. Med njimi izstopata predvsem obmembranska domena, ki jo vsebuje tudi najbližji homolog ADAM10, in regija CANDIS, ki je edinstvena lastnost tega encima. Regulacija aktivnosti ADAM17 je kompleksna, pri njej pa so pomembne tudi posamezne domene oz. njihova konformacija, ki se tekom življenjske dobe proteina spreminja. ADAM17 obstaja v dveh oblikah: odprti, aktivni, in zaprti, neaktivni. Da bi dobili vpogled v strukturo ADAM17, ki sicer ni znana, in v interakcijo s substratom EpCAM, smo s programi za napovedovanje struktur najprej naredili modele celotne zunajcelične domene in treh njenih skrajšanih oblik: CAT (vsebuje katalitično domeno), CAT-DIS (vsebuje katalitično in disintegrinsko domeno) in CAT-DIS-MPD (vsebuje katalitično, disintegrinsko in obmembransko domeno). S programi za molekulsko umeščanje smo ugotovili, da se lahko EpCAM na ADAM17 veže tudi, ko je ADAM17 v zaprti obliki, in da fleksibilna zanka na EpCAM ne vpliva na vezavo. Rezultati kažejo tudi, da predstavlja regija CANDIS pomemben strukturni regulatorni element, ki v zaprti obliki ADAM17 prepreči katalizo, saj se orientira tako, da aktivnemu mestu na ADAM17 ovira dostop do cepitvenega mesta na EpCAM.
Language:
Slovenian
Keywords:
ADAM17
,
zunajcelična domena
,
EpCAM
,
odcep ektodomene
,
regulacija encimske aktivnosti
Work type:
Bachelor thesis/paper
Typology:
2.11 - Undergraduate Thesis
Organization:
FKKT - Faculty of Chemistry and Chemical Technology
Year:
2020
PID:
20.500.12556/RUL-119545
COBISS.SI-ID:
29842435
Publication date in RUL:
09.09.2020
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1616
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186
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Language:
English
Title:
Bioinformatic analysis of the extracellular domain of ADAM17 and cloning of its truncated variants
Abstract:
ADAM17 is a transmembrane metalloprotease with a major role in numerous physiological and pathophysiological processes. It facilitates cell signalling by catalysing ectodomain shedding of various transmembrane substrates which is usually followed by regulated intramembrane proteolysis. It can also bind to α5β1-integrin and therefore support cell-cell interaction. The mature extracellular domain of ADAM17 consists of catalytic-, disintegrin- and membrane-proximal domain with additional short C-terminal region termed CANDIS. A homologous membrane-proximal domain can additionally only be found in ADAM10, the closest relative of ADAM17, while CANDIS is a unique ADAM17 feature. The regulation of ADAM17 activity is complex and the changing conformation of its domains represents its crucial part. ADAM17 exists either in active open form or inactive closed form. To gain insight in yet unknown structure of ADAM17 and its interaction with substrate EpCAM, we firstly used protein structure prediction programs to create models of the extracellular domain of ADAM17 and its truncated variants: CAT (including catalytical domain), CAT-DIS (including catalytical- and disintegrin domain) and CAT-DIS-MPD (including catalytical-, disintegrin- and membrane-proximal domain). By utilizing molecular docking programs, we showed that the interaction between EpCAM and ADAM17 can also occur when ADAM17 is in its closed form. Furthermore, the results also indicate that CANDIS is an essential structural regulatory element disabling ADAM17 closed form’s activity by obstructing interaction space for EpCAM binding.
Keywords:
ADAM17
,
extracellular domain
,
EpCAM
,
ectodomain shedding
,
regulation of enzyme activity
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