A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F23%3A00572295" target="_blank" >RIV/68378050:_____/23:00572295 - isvavai.cz</a>

Výsledek na webu

<a href="https://link.springer.com/article/10.1007/s00018-023-04783-y" target="_blank" >https://link.springer.com/article/10.1007/s00018-023-04783-y</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00018-023-04783-y" target="_blank" >10.1007/s00018-023-04783-y</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

Popis výsledku v původním jazyce

Several membrane-anchored signal mediators such as cytokines (e.g. TNF alpha) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which, thus, has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways.

Název v anglickém jazyce

A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

Popis výsledku anglicky

Several membrane-anchored signal mediators such as cytokines (e.g. TNF alpha) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which, thus, has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LM2018126" target="_blank" >LM2018126: České centrum pro fenogenomiku</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cellular and Molecular Life Sciences

ISSN

1420-682X

e-ISSN

1420-9071

Svazek periodika

80

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

21

Strana od-do

135

Kód UT WoS článku

000978465900001

EID výsledku v databázi Scopus

2-s2.0-85156136892