CL-11 circulates in serum as functionally distinct isoforms
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CL-11 circulates in serum as functionally distinct isoforms. / Sutta, Adrian; Leemans, Nelia Nina; Ploug, Michael; Rosbjerg, Anne; del Agua Villa, Christian; Pérez-Alós, Laura; Cyranka, Leon; Vincek, Adam S.; de Garay, Tomás; Rivera, Keith; Bayarri-Olmos, Rafael.
I: FASEB Journal, Bind 38, Nr. 5, e23543, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - CL-11 circulates in serum as functionally distinct isoforms
AU - Sutta, Adrian
AU - Leemans, Nelia Nina
AU - Ploug, Michael
AU - Rosbjerg, Anne
AU - del Agua Villa, Christian
AU - Pérez-Alós, Laura
AU - Cyranka, Leon
AU - Vincek, Adam S.
AU - de Garay, Tomás
AU - Rivera, Keith
AU - Bayarri-Olmos, Rafael
N1 - Publisher Copyright: © 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2024
Y1 - 2024
N2 - Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway capable of interacting with collectin-10 (CL-10) and the MASPs to activate the complement cascade. Alternative splicing of the COLEC11 gene gives rise to two different isoforms found in serum (A and D). These isoforms vary in the length of their collagen-like region, which is involved in the stabilization of the trimeric subunit and the interaction with the MASPs. Here we aim at elucidating the biological differences of naturally occurring CL-11 isoforms A and D. We produced recombinant CL-11 as independent isoforms (CL-11A and CL-11D) and together with CL-10 (CL-10/11A, CL-10/11D). Both CL-11 isoforms associated with CL-10, but CL-11D did so to a lesser extent. CL-10/11 heterocomplexes were composed of trimeric subunits of CL-10 and CL-11, as opposed to CL-10 and CL-11 homotrimers. Heterocomplexes were more stable and migrated with higher apparent molecular weights. Immunoprecipitation of serum CL-11 and subsequent mass spectrometry analysis confirmed that native CL-11 circulates in the form of CL-10/11 heterocomplexes that associate with MASP-1, and MASP-3, but not necessarily MASP-2. Despite a shorter collagen region, CL-11D was capable to bind to the MASPs, suggesting that the missing exon 4 is not required for MASP association CL-11D had a reduced ligand binding compared to full-length CL-11A. Based on its reduced ability to oligomerize, form CL-10/11 heterocomplexes, and bind to ligands, we hypothesize that CL-11D may have a limited complement activation potential compared to full-length CL-11A.
AB - Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway capable of interacting with collectin-10 (CL-10) and the MASPs to activate the complement cascade. Alternative splicing of the COLEC11 gene gives rise to two different isoforms found in serum (A and D). These isoforms vary in the length of their collagen-like region, which is involved in the stabilization of the trimeric subunit and the interaction with the MASPs. Here we aim at elucidating the biological differences of naturally occurring CL-11 isoforms A and D. We produced recombinant CL-11 as independent isoforms (CL-11A and CL-11D) and together with CL-10 (CL-10/11A, CL-10/11D). Both CL-11 isoforms associated with CL-10, but CL-11D did so to a lesser extent. CL-10/11 heterocomplexes were composed of trimeric subunits of CL-10 and CL-11, as opposed to CL-10 and CL-11 homotrimers. Heterocomplexes were more stable and migrated with higher apparent molecular weights. Immunoprecipitation of serum CL-11 and subsequent mass spectrometry analysis confirmed that native CL-11 circulates in the form of CL-10/11 heterocomplexes that associate with MASP-1, and MASP-3, but not necessarily MASP-2. Despite a shorter collagen region, CL-11D was capable to bind to the MASPs, suggesting that the missing exon 4 is not required for MASP association CL-11D had a reduced ligand binding compared to full-length CL-11A. Based on its reduced ability to oligomerize, form CL-10/11 heterocomplexes, and bind to ligands, we hypothesize that CL-11D may have a limited complement activation potential compared to full-length CL-11A.
KW - CL-10
KW - CL-11
KW - collectin
KW - complement system
KW - lectin pathway
KW - MASP
U2 - 10.1096/fj.202301765R
DO - 10.1096/fj.202301765R
M3 - Journal article
C2 - 38466278
AN - SCOPUS:85187882864
VL - 38
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 5
M1 - e23543
ER -
ID: 386196545