The　proteins　of　the　mannose　receptor　(MR)　family　share　a　common　domain　organization　and　have　a　broad　range　of　biological　functions.　Urokinase　plasminogen　activator　receptor-associated　protein　(uPARAP)　(or　Endo180)　is　a　member　of　this　family　and　plays　an　important　role　in　extracellular　matrix　remodelling　through　interaction　with　its　ligands,　including　collagens　and　urokinase　plasminogen　activator　receptor　(uPAR).　We　report　the　crystal　structures　of　the　first　four　domains　of　uPARAP　(also　named　the　ligand-binding　region,　LBR)　at　pH　7.4　in　Ca2+-bound　and　Ca2+-free　forms.　The　first　domain　(cysteine-rich　or　CysR　domain)　folds　into　a　new　and　unique　conformation　different　from　the　beta-trefoil　fold　of　typical　CysR　domains.　The　so-called　long　loop　regions　(LLRs)　of　the　C-type　lectin-like　domain　(CTLD)　1　and　2　(the　third　and　fourth　domain)　mediate　the　direct　contacts　between　these　domains.　These　LLRs　undergo　a　Ca2+　dependent　conformational　change,　and　this　is　likely　to　be　the　key　structural　determinant　affecting　the　overall　conformation　of　uPARAP.　Our　results　provide　a　molecular　mechanism　to　support　the　structural　flexibility　of　uPARAP,　and　shed　light　on　the　structural　flexibility　of　other　members　of　the　MR　family.