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Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis

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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.
Original languageEnglish
JournalThe journal of biological chemistry
Pages (from-to)7935-7947
ISSN0021-9258
DOIs
Publication statusPublished - 14 Mar 2014

ID: 42873501