E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  175 TPTPRPTDGVDVYFEMPGDGNEHANFLRAKMDLEERRMKQINEVMKEWAEADNEAKNLPKTD-------RQALN------ 241
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTarfqet 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  242 -ETLEEQVAGERQRLVETHLARVVALLNDNRRAALENYLTAVQNDHAQPDRILAALKRYVRAEQKDQRHTLRHYQH---- 316
Cdd:pfam12925  81 vEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHllas 160

                         170       180
                  ....*....|....*....|....*...
gi 565314197  317 NPQLTQELRGDIEELLRSERVSTNDLLT 344
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLT 188

Copper-binding of amyloid precursor, CuBD; This short domain, part of the extra-cellular N-terminus of the amyloid precursor protein, APP, can bind both copper and zinc, CuBD. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavourable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 565314197    1 MDSCETYLYWHSVAKEACSGEHLELHSYGMLLPCGADRFRGVEYVCCP 48
Cdd:pfam12924   9 MDVCESHQHWHATAKEACAARGMVLHSFGMLLPCGIDLFTGVEFVCCP 56

E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  175 TPTPRPTDGVDVYFEMPGDGNEHANFLRAKMDLEERRMKQINEVMKEWAEADNEAKNLPKTD-------RQALN------ 241
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTarfqet 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  242 -ETLEEQVAGERQRLVETHLARVVALLNDNRRAALENYLTAVQNDHAQPDRILAALKRYVRAEQKDQRHTLRHYQH---- 316
Cdd:pfam12925  81 vEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHllas 160

                         170       180
                  ....*....|....*....|....*...
gi 565314197  317 NPQLTQELRGDIEELLRSERVSTNDLLT 344
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLT 188

Copper-binding of amyloid precursor, CuBD; This short domain, part of the extra-cellular N-terminus of the amyloid precursor protein, APP, can bind both copper and zinc, CuBD. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavourable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 565314197    1 MDSCETYLYWHSVAKEACSGEHLELHSYGMLLPCGADRFRGVEYVCCP 48
Cdd:pfam12924   9 MDVCESHQHWHATAKEACAARGMVLHSFGMLLPCGIDLFTGVEFVCCP 56

amyloid A4; amyloid A4 precursor of Alzheimers disease

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 565314197     1 MDSCETYLYWHSVAKEACSGEHLELHSYGMLLPCGADRFRGVEYVCCP 48
Cdd:smart00006 118 MDQCETHQRWHQEAKEACSEKGMILHSFGMLLPCGIDKFRGVEFVCCP 165

E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  175 TPTPRPTDGVDVYFEMPGDGNEHANFLRAKMDLEERRMKQINEVMKEWAEADNEAKNLPKTD-------RQALN------ 241
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTarfqet 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565314197  242 -ETLEEQVAGERQRLVETHLARVVALLNDNRRAALENYLTAVQNDHAQPDRILAALKRYVRAEQKDQRHTLRHYQH---- 316
Cdd:pfam12925  81 vEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHllas 160

                         170       180
                  ....*....|....*....|....*...
gi 565314197  317 NPQLTQELRGDIEELLRSERVSTNDLLT 344
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLT 188

juxtamembrane and transmembrane (JMTM) domain found in amyloid-like protein 2 (APLP-2) and similar proteins; Amyloid-like protein 2 (APLP-2), also called amyloid protein homolog (APPH), or CDEI box-binding protein (CDEBP), may play a role in the regulation of hemostasis. Its soluble form may have inhibitory properties towards coagulation factors. APLP-2 may bind to the DNA 5'-GTCACATG-3'(CDEI box). It inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein. This model corresponds to juxtamembrane and transmembrane (JMTM) domain of APLP-2, which consists of the intact transmembrane (TM) domain with adjacent N-terminal juxtamembrane (JM) region.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 565314197 430 GALIGLLIVAVAVAMVIIISLLMVRRKPYGTISHGIVEVDPMVSPEERQLNKMQNHGYENPTYKFFEE 497
Cdd:cd21709   14 SALIGLLVIAVAIATVIVISLVLLRKRQYGTISHGIVEVDPMLTPEERHLNKMQNHGYENPTYKYLEQ 81

Beta-amyloid precursor protein C-terminus; This is the amyloid, C-terminal, protein of the beta-Amyloid precursor protein (APP) which is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. The C-terminal 100 residues are released and aggregate into amyloid deposits which are strongly implicated in the pathology of Alzheimer's disease plaque-formation. The domain is associated with family A4_EXTRA, pfam02177, further towards the N-terminus.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 565314197  446 IIISLLMVRRK-PYGTISHGIVEVDPMVSPEERQLNKMQNHGYENPTYKFFE 496
Cdd:pfam10515   1 IVVGMALLRRRaARSPSAHGFVEVDPNVTPEERHVANMQVNGYENPTYKYFE 52

juxtamembrane and transmembrane (JMTM) domain found in the amyloid-beta precursor protein (APP) family; The amyloid-beta precursor protein (APP) family includes amyloid-like proteins APLP-1 and APLP-2. APP (also called ABPP, APPI, Alzheimer disease (AD) amyloid protein, amyloid precursor protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), PreA4, or protease nexin-II (PN-II)) functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity; they bind transient metals such as copper, zinc and iron. APLP-1, also called APLP, may play a role in postsynaptic function. It couples to JIP signal transduction through C-terminal binding. APLP-1 may interact with cellular G-protein signaling pathways. It can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I. APLP-2 (also called amyloid protein homolog (APPH), or CDEI box-binding protein (CDEBP)) may play a role in the regulation of hemostasis. Its soluble form may have inhibitory properties towards coagulation factors. APLP-2 may bind to the DNA 5'-GTCACATG-3'(CDEI box). It inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein. This model corresponds to juxtamembrane and transmembrane (JMTM) domain of APP, which consists of the intact transmembrane (TM) domain with adjacent N-terminal juxtamembrane (JM) region. More than half of all familial APP mutations of Alzheimer's disease are seen in its JMTM domain region.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 565314197 415 QRDELEPDTlVTINRGALIGLLIVAVAVAMVIIISLLMVRRK 456
Cdd:cd21699    1 ERVFLAEDS-SNSSFGAVIGLAVGGVAVAIVIVVAVVMLRRR 41