Receptor　dimerization　of　urokinase-type　plasminogen　activator　receptor　(uPAR)　was　previously　identified　at　protein　level　and　on　cell　surface.　Recently,　a　dimeric　form　of　mouse　uPAR　isoform　2　was　proposed　to　induce　kidney　disease.　Here,　we　report　the　crystal　structure　of　human　uPAR　dimer　at　2.96　angstrom.　The　structure　reveals　enormous　conformational　changes　of　the　dimer　compared　to　the　monomeric　structure:　D1　of　uPAR　opens　up　into　a　large　expanded　ring　that　captures　a　beta-hairpin　loop　of　a　neighboring　uPAR　to　form　an　expanded　beta-sheet,　leading　to　an　elongated,　highly　intertwined　dimeric　uPAR.　Based　on　the　structure,　we　identify　E49P　as　a　mutation　promoting　dimer　formation.　The　mutation　increases　receptor　binding　to　the　amino　terminal　fragment　of　its　primary　ligand　uPA,　induces　the　receptor　to　distribute　to　the　basal　membrane,　promotes　cell　proliferation,　and　alters　cell　morphology　via　beta　1　integrin　signaling.　These　results　reveal　the　structural　basis　for　uPAR　dimerization,　its　effect　on　cellular　functions,　and　provide　a　basis　to　further　study　this　multifunctional　receptor.　The　structural　basis　for　urokinase-type　plasminogen　activator　receptor　(uPAR)　dimerization　is　not　understood.　Here,　the　authors　solve　the　crystal　structure　of　soluble　uPAR　dimers,　identifying　substantial　structural　changes　compared　to　the　monomer.