Ly6/uPAR/α-neurotoxin　domain　(LU-domain)　is　characterized　by　the　presence　of　4–5　disulfide　bonds　and　three　flexible　loops　that　extend　from　a　core　stacked　by　several　conversed　disulfide　bonds　(thus　also　named　three-fingered　protein　domain).　This　highly　structurally　stable　protein　domain　is　typically　a　protein-binder　at　extracellular　space.　Most　LU　proteins　contain　only　single　LU-domain　as　represented　by　Ly6　proteins　in　immunology　and　α-neurotoxins　in　snake　venom.　For　Ly6　proteins,　many　are　expressed　in　specific　cell　lineages　and　in　differentiation　stages,　and　are　used　as　markers.　In　this　study,　we　report　the　crystal　structures　of　the　two　LU-domains　of　human　C4.4A　alone　and　its　complex　with　a　Fab　fragment　of　a　monoclonal　anti-C4.4A　antibody.　Interestingly,　both　structures　showed　that　C4.4A　forms　a　very　compact　globule　with　two　LU-domain　packed　face　to　face.　This　is　in　contrast　to　the　flexible　nature　of　most　LU-domain-containing　proteins　in　mammals.　The　Fab　combining　site　of　C4.4A　involves　both　LU-domains,　and　appears　to　be　the　binding　site　for　AGR2,　a　reported　ligand　of　C4.4A.　This　work　reports　the　first　structure　that　contain　two　LU-domains　and　provides　insights　on　how　LU-domains　fold　into　a　compact　protein　and　interacts　with　ligands.　©　The　author(s).