Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis
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Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis. / Jürgensen, Henrik J.; Johansson, Kristina; Madsen, Daniel H; Porse, Astrid; Melander, Maria C; Sørensen, Kristine R.; Nielsen, Christoffer; Bugge, Thomas H; Behrendt, Niels; Engelholm, Lars H.
In: The Journal of Biological Chemistry, Vol. 289, No. 11, 2014, p. 7935-7947.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis
AU - Jürgensen, Henrik J.
AU - Johansson, Kristina
AU - Madsen, Daniel H
AU - Porse, Astrid
AU - Melander, Maria C
AU - Sørensen, Kristine R.
AU - Nielsen, Christoffer
AU - Bugge, Thomas H
AU - Behrendt, Niels
AU - Engelholm, Lars H.
PY - 2014
Y1 - 2014
N2 - Members of the well-conserved mannose receptor (MR) protein family have been functionally implicated in diverse biological and pathological processes. Importantly, a proposed common function is the internalization of collagen for intracellular degradation occurring during bone development, cancer invasion, and fibrosis protection. This functional relationship is suggested by a common endocytic capability and a candidate collagen-binding domain. Here we conducted a comparative investigation of each member's ability to facilitate intracellular collagen degradation. As expected, the family members uPARAP/Endo180 and MR bound collagens in a purified system and internalized collagens for degradation in cellular settings. In contrast, the remaining family members, PLA2R and DEC-205, showed no collagen binding activity and were unable to mediate collagen internalization. To pinpoint the structural elements discriminating collagen from non-collagen receptors, we constructed a series of receptor chimeras and loss- and gain-of-function mutants. Using this approach we identified a critical collagen binding loop in the suggested collagen binding region (an FN-II domain) in uPARAP/Endo180 and MR, which was different in PLA2R or DEC-205. However, we also found that an active FN-II domain was not a sufficient determinant to allow collagen internalization through these receptors. Nevertheless, this ability could be acquired by the transfer of a larger segment of uPARAP/Endo180 (the Cys-rich domain, the FN-II domain and two CTLDs) to DEC-205. These data underscore the importance of the FN-II domain in uPARAP/Endo180 and MR-mediated collagen internalization but at the same time uncover a critical interplay with flanking domains.
AB - Members of the well-conserved mannose receptor (MR) protein family have been functionally implicated in diverse biological and pathological processes. Importantly, a proposed common function is the internalization of collagen for intracellular degradation occurring during bone development, cancer invasion, and fibrosis protection. This functional relationship is suggested by a common endocytic capability and a candidate collagen-binding domain. Here we conducted a comparative investigation of each member's ability to facilitate intracellular collagen degradation. As expected, the family members uPARAP/Endo180 and MR bound collagens in a purified system and internalized collagens for degradation in cellular settings. In contrast, the remaining family members, PLA2R and DEC-205, showed no collagen binding activity and were unable to mediate collagen internalization. To pinpoint the structural elements discriminating collagen from non-collagen receptors, we constructed a series of receptor chimeras and loss- and gain-of-function mutants. Using this approach we identified a critical collagen binding loop in the suggested collagen binding region (an FN-II domain) in uPARAP/Endo180 and MR, which was different in PLA2R or DEC-205. However, we also found that an active FN-II domain was not a sufficient determinant to allow collagen internalization through these receptors. Nevertheless, this ability could be acquired by the transfer of a larger segment of uPARAP/Endo180 (the Cys-rich domain, the FN-II domain and two CTLDs) to DEC-205. These data underscore the importance of the FN-II domain in uPARAP/Endo180 and MR-mediated collagen internalization but at the same time uncover a critical interplay with flanking domains.
KW - Amino Acid Sequence
KW - Animals
KW - Cell Line
KW - Collagen
KW - Drosophila
KW - Endocytosis
KW - Fibroblasts
KW - HEK293 Cells
KW - HeLa Cells
KW - Humans
KW - Insects
KW - Lectins, C-Type
KW - Ligands
KW - Mannose-Binding Lectins
KW - Membrane Glycoproteins
KW - Mice
KW - Molecular Sequence Data
KW - Plasmids
KW - Protein Binding
KW - Protein Structure, Tertiary
KW - Receptors, Cell Surface
KW - Receptors, Mitogen
KW - Sequence Homology, Amino Acid
KW - Structure-Activity Relationship
U2 - 10.1074/jbc.M113.512780
DO - 10.1074/jbc.M113.512780
M3 - Journal article
C2 - 24500714
VL - 289
SP - 7935
EP - 7947
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 11
ER -
ID: 140433336