1TAW

BOVINE TRYPSIN COMPLEXED TO APPI

External Resource: Annotation

Domain Annotation: SCOP/SCOPe Classification
Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP/SCOPe Classification SCOP-e Database Homepage

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
B	d1tawb_	Small proteins	BPTI-like	BPTI-like	Small Kunitz-type inhibitors & BPTI-like toxins	Alzheimer's amyloid B-protein precursor, APPI	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
A	d1tawa_	All beta proteins	Trypsin-like serine proteases	Trypsin-like serine proteases	Eukaryotic proteases	Trypsin(ogen)	(Bos taurus ) [TaxId: 9913 ],	SCOPe (2.08)

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
B	SCOP2B Superfamily	BPTI-like	8038527	3000628	SCOP2B (2022-06-29)
A	SCOP2B Superfamily	Trypsin-like serine proteases	8037496	3000114	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
B	Kunitz_BPTI	e1tawB1	A: few secondary structure elements	X: BPTI-like (From Topology)	H: BPTI-like (From Topology)	T: BPTI-like	F: Kunitz_BPTI	ECOD (1.6)
A	Trypsin_1	e1tawA1	A: beta barrels	X: cradle loop barrel	H: RIFT-related	T: FMN-binding split barrel 2	F: Trypsin_1	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
B	4.10.410.10	Few Secondary Structures	Irregular	Factor Xa Inhibitor	Pancreatic trypsin inhibitor Kunitz domain	CATH (4.3.0)
A	2.40.10.10	Mainly Beta	Beta Barrel	Thrombin, subunit H	Trypsin-like serine proteases	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
B	PF00014	Kunitz/Bovine pancreatic trypsin inhibitor domain (Kunitz_BPTI)	Kunitz/Bovine pancreatic trypsin inhibitor domain	Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the ...	Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP, Swiss:P17726). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways [1]. TAP molecules are highly dipolar [2], and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix [1].	Domain
A	PF00089	Trypsin (Trypsin)	Trypsin	-	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
B	PROTEASE INHIBITOR DOMAIN OF ALZHEIMER'S AMYLOID BETA-PROTEIN PRECURSOR	DNA binding binding organic cyclic compound binding nucleic acid binding protein binding signaling receptor binding cation binding transition metal ion binding ion binding metal ion binding small molecule binding PTB domain binding protein domain specific binding identical protein binding DNA binding binding organic cyclic compound binding nucleic acid binding protein binding signaling receptor binding cation binding transition metal ion binding ion binding metal ion binding small molecule binding PTB domain binding protein domain specific binding identical protein binding molecular function activator activity molecular function regulator activity signaling receptor regulator activity receptor ligand activity signaling receptor activator activity sequence-specific DNA binding double-stranded DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding cis-regulatory region sequence-specific DNA binding sequence-specific double-stranded DNA binding transcription cis-regulatory region binding transcription regulatory region nucleic acid binding RNA polymerase II cis-regulatory region sequence-specific DNA binding enzyme regulator activity molecular function inhibitor activity peptidase regulator activity serine-type endopeptidase inhibitor activity enzyme inhibitor activity peptidase inhibitor activity endopeptidase regulator activity endopeptidase inhibitor activity protein serine/threonine kinase binding kinase binding enzyme binding protein kinase binding heparin binding glycosaminoglycan binding carbohydrate derivative binding sulfur compound binding	negative regulation of long-term synaptic potentiation positive regulation of cell communication regulation of cellular process modulation of chemical synaptic transmission signaling positive regulation of biological process negative regulation of biological process cell communication long-term synaptic potentiation synaptic signaling regulation of biological quality positive regulation of cellular process regulation of synaptic plasticity trans-synaptic signaling negative regulation of long-term synaptic potentiation positive regulation of cell communication regulation of cellular process modulation of chemical synaptic transmission signaling positive regulation of biological process negative regulation of biological process cell communication long-term synaptic potentiation synaptic signaling regulation of biological quality positive regulation of cellular process regulation of synaptic plasticity trans-synaptic signaling regulation of biological process regulation of signaling biological regulation cell-cell signaling positive regulation of synaptic transmission chemical synaptic transmission regulation of trans-synaptic signaling anterograde trans-synaptic signaling regulation of long-term synaptic potentiation regulation of cell communication cellular process positive regulation of signaling regulation of synapse structure or activity cellular response to stimulus multicellular organismal process regulation of postsynaptic membrane potential system process response to stimulus regulation of system process regulation of signal transduction chemical synaptic transmission, postsynaptic modulation of excitatory postsynaptic potential regulation of multicellular organismal process signal transduction cell surface receptor signaling pathway nervous system process regulation of nervous system process regulation of response to stimulus excitatory postsynaptic potential regulation of membrane potential positive regulation of signal transduction intracellular signal transduction positive regulation of response to stimulus regulation of intracellular signal transduction intracellular signaling cassette regulation of calcium-mediated signaling positive regulation of calcium-mediated signaling positive regulation of intracellular signal transduction calcium-mediated signaling cellular component organization extracellular matrix organization cellular component organization or biogenesis extracellular structure organization external encapsulating structure organization positive regulation of phosphorylation regulation of protein modification process regulation of protein phosphorylation positive regulation of protein metabolic process regulation of peptidyl-serine phosphorylation positive regulation of phosphate metabolic process peptidyl-serine modification regulation of primary metabolic process positive regulation of metabolic process positive regulation of protein modification process peptidyl-serine phosphorylation regulation of phosphate metabolic process phosphate-containing compound metabolic process peptidyl-amino acid modification positive regulation of macromolecule metabolic process protein metabolic process positive regulation of protein phosphorylation phosphorus metabolic process protein modification process protein phosphorylation positive regulation of phosphorus metabolic process phosphorylation regulation of protein metabolic process primary metabolic process regulation of macromolecule metabolic process positive regulation of peptidyl-serine phosphorylation macromolecule modification regulation of phosphorus metabolic process metabolic process regulation of phosphorylation macromolecule metabolic process regulation of metabolic process regulation of multicellular organism growth developmental process regulation of growth regulation of developmental growth regulation of developmental process developmental growth growth multicellular organism growth axonogenesis cellular developmental process cell projection organization plasma membrane bounded cell projection morphogenesis cell development neuron projection development cell morphogenesis neurogenesis multicellular organism development cell projection morphogenesis neuron differentiation neuron projection morphogenesis cell differentiation anatomical structure development system development plasma membrane bounded cell projection organization nervous system development axon development cell morphogenesis involved in neuron differentiation generation of neurons anatomical structure morphogenesis neuron development cell growth collateral sprouting in absence of injury collateral sprouting developmental cell growth developmental growth involved in morphogenesis positive regulation of macromolecule biosynthetic process positive regulation of biosynthetic process regulation of cytokine production cytokine production regulation of biosynthetic process gene expression macromolecule biosynthetic process regulation of chemokine production regulation of gene expression biosynthetic process positive regulation of gene expression chemokine production positive regulation of chemokine production positive regulation of multicellular organismal process regulation of macromolecule biosynthetic process positive regulation of cytokine production behavior suckling behavior feeding behavior astrocyte differentiation astrocyte activation glial cell development astrocyte development gliogenesis response to stress defense response cell activation central nervous system development glial cell differentiation glial cell activation inflammatory response neuroinflammatory response Notch signaling pathway cell cycle G2/M phase transition mitotic cell cycle process G2/M transition of mitotic cell cycle cell cycle phase transition cell cycle mitotic cell cycle cell cycle process mitotic cell cycle phase transition myeloid leukocyte activation leukocyte activation macrophage activation immune system process leukocyte activation involved in inflammatory response microglial cell activation cellular homeostasis neuron cellular homeostasis homeostatic process neuron recognition axon choice point recognition cell recognition axon midline choice point recognition axon guidance neuron projection guidance ribonucleotide catabolic process pyridine nucleotide catabolic process oxoacid metabolic process carbohydrate catabolic process carbohydrate derivative metabolic process organophosphate catabolic process regulation of generation of precursor metabolites and energy nucleoside phosphate catabolic process organic acid metabolic process regulation of ATP metabolic process nucleobase-containing compound metabolic process regulation of purine nucleotide catabolic process positive regulation of nucleotide catabolic process regulation of small molecule metabolic process glycolytic process regulation of nucleotide metabolic process pyridine-containing compound metabolic process small molecule metabolic process regulation of nucleobase-containing compound metabolic process purine ribonucleotide catabolic process pyridine nucleotide metabolic process nucleoside phosphate metabolic process nicotinamide nucleotide metabolic process pyruvate metabolic process regulation of carbohydrate catabolic process positive regulation of nucleobase-containing compound metabolic process purine nucleoside diphosphate metabolic process purine-containing compound catabolic process nucleotide metabolic process regulation of purine nucleotide metabolic process nucleobase-containing compound catabolic process positive regulation of ATP metabolic process nucleoside diphosphate metabolic process purine nucleoside diphosphate catabolic process nucleoside diphosphate catabolic process regulation of nucleotide catabolic process nucleoside triphosphate metabolic process positive regulation of carbohydrate metabolic process monocarboxylic acid metabolic process purine ribonucleotide metabolic process pyridine-containing compound catabolic process ribose phosphate metabolic process ATP metabolic process catabolic process positive regulation of nucleotide metabolic process positive regulation of purine nucleotide catabolic process purine nucleotide metabolic process ribonucleotide metabolic process nucleobase-containing small molecule metabolic process purine ribonucleoside triphosphate metabolic process ribonucleoside diphosphate metabolic process ribonucleoside diphosphate catabolic process regulation of carbohydrate metabolic process ribonucleoside triphosphate metabolic process nucleotide catabolic process purine nucleoside triphosphate metabolic process carbohydrate metabolic process purine nucleotide catabolic process carbohydrate derivative catabolic process positive regulation of glycolytic process ADP catabolic process carboxylic acid metabolic process generation of precursor metabolites and energy regulation of catabolic process regulation of glycolytic process purine-containing compound metabolic process positive regulation of purine nucleotide metabolic process positive regulation of catabolic process ADP metabolic process organophosphate metabolic process purine ribonucleoside diphosphate metabolic process positive regulation of small molecule metabolic process purine ribonucleoside diphosphate catabolic process myeloid leukocyte differentiation mononuclear cell differentiation microglia differentiation hemopoiesis macrophage differentiation microglia development myeloid cell differentiation myeloid cell development leukocyte differentiation regulation of cellular component organization positive regulation of cellular component organization positive regulation of amyloid fibril formation regulation of amyloid fibril formation amyloid fibril formation positive regulation of supramolecular fiber organization regulation of supramolecular fiber organization supramolecular fiber organization positive regulation of ERK1 and ERK2 cascade positive regulation of MAPK cascade regulation of MAPK cascade MAPK cascade ERK1 and ERK2 cascade regulation of ERK1 and ERK2 cascade positive regulation of long-term synaptic potentiation regulation of peptidyl-threonine phosphorylation peptidyl-threonine modification positive regulation of peptidyl-threonine phosphorylation peptidyl-threonine phosphorylation cellular localization transport intracellular transport establishment of localization localization axo-dendritic transport establishment of localization in cell microtubule-based transport transport along microtubule cytoskeleton-dependent intracellular transport microtubule-based movement microtubule-based process neuromuscular process neuromuscular process controlling balance organic hydroxy compound metabolic process sterol metabolic process steroid metabolic process cholesterol metabolic process alcohol metabolic process secondary alcohol metabolic process lipid metabolic process cell junction organization synapse organization head development forebrain development animal organ development brain development regulation of Wnt signaling pathway Wnt signaling pathway neuron apoptotic process apoptotic process cell death programmed cell death ligand-gated ion channel signaling pathway ionotropic glutamate receptor signaling pathway glutamate receptor signaling pathway regulation of non-canonical NF-kappaB signal transduction non-canonical NF-kappaB signal transduction positive regulation of non-canonical NF-kappaB signal transduction cell activation involved in immune response astrocyte activation involved in immune response immune response immune effector process negative regulation of metabolic process negative regulation of gene expression negative regulation of biosynthetic process negative regulation of macromolecule biosynthetic process negative regulation of cellular process negative regulation of macromolecule metabolic process positive regulation of cell cycle regulation of mitotic cell cycle positive regulation of mitotic cell cycle regulation of cell cycle regulation of tumor necrosis factor production positive regulation of tumor necrosis factor superfamily cytokine production tumor necrosis factor superfamily cytokine production positive regulation of tumor necrosis factor production tumor necrosis factor production regulation of tumor necrosis factor superfamily cytokine production response to oxidative stress neuron projection maintenance neuron projection organization cellular response to nitrogen compound response to oxygen-containing compound response to nitrogen compound cellular response to amyloid-beta cellular response to oxygen-containing compound cellular response to chemical stimulus response to chemical response to amyloid-beta regulation of cell cycle phase transition positive regulation of mitotic cell cycle phase transition positive regulation of cell cycle process positive regulation of G2/M transition of mitotic cell cycle regulation of G2/M transition of mitotic cell cycle regulation of cell cycle process regulation of cell cycle G2/M phase transition positive regulation of cell cycle G2/M phase transition regulation of mitotic cell cycle phase transition positive regulation of cell cycle phase transition regulation of cell differentiation negative regulation of cell differentiation negative regulation of developmental process negative regulation of neuron differentiation regulation of neuron differentiation learning learning or memory cognition regulation of defense response regulation of response to external stimulus response to external stimulus regulation of inflammatory response positive regulation of response to external stimulus positive regulation of inflammatory response regulation of response to stress positive regulation of defense response inorganic ion homeostasis intracellular copper ion homeostasis copper ion homeostasis chemical homeostasis intracellular monoatomic cation homeostasis monoatomic ion homeostasis intracellular chemical homeostasis monoatomic cation homeostasis intracellular monoatomic ion homeostasis developmental maturation neuron remodeling anatomical structure maturation neuron maturation cell maturation reproductive process multicellular organismal reproductive process reproductive behavior mating behavior peptidyl-tyrosine modification regulation of peptidyl-tyrosine phosphorylation peptidyl-tyrosine phosphorylation translation post-transcriptional regulation of gene expression regulation of translation interleukin-1 production regulation of interleukin-1 beta production positive regulation of interleukin-1 beta production positive regulation of interleukin-1 production regulation of interleukin-1 production interleukin-1 beta production regulation of neuronal synaptic plasticity regulation of long-term neuronal synaptic plasticity positive regulation of JNK cascade JNK cascade regulation of JNK cascade positive regulation of locomotion regulation of cell motility regulation of lymphocyte migration positive regulation of cell migration positive regulation of cell motility regulation of cell migration positive regulation of mononuclear cell migration cell migration regulation of immune system process cell motility regulation of mononuclear cell migration positive regulation of immune system process locomotion positive regulation of lymphocyte migration regulation of leukocyte migration positive regulation of T cell migration lymphocyte migration positive regulation of leukocyte migration leukocyte migration regulation of locomotion regulation of T cell migration mononuclear cell migration T cell migration cell adhesion NMDA selective glutamate receptor signaling pathway positive regulation of DNA-templated transcription RNA metabolic process RNA biosynthetic process nucleic acid biosynthetic process DNA-templated transcription regulation of RNA metabolic process transcription by RNA polymerase II regulation of RNA biosynthetic process regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II nucleobase-containing compound biosynthetic process nucleic acid metabolic process positive regulation of RNA metabolic process positive regulation of RNA biosynthetic process regulation of DNA-templated transcription locomotory behavior adult locomotory behavior adult behavior cytosolic mRNA polyadenylation mRNA metabolic process interleukin-6 production positive regulation of interleukin-6 production regulation of interleukin-6 production import into cell endocytosis vesicle-mediated transport regulation of presynapse assembly cellular component biogenesis regulation of presynapse organization cellular component assembly cell junction assembly regulation of synapse assembly presynapse organization regulation of cellular component biogenesis regulation of cell junction assembly regulation of synapse organization synapse assembly presynapse assembly spontaneous synaptic transmission regulation of spontaneous synaptic transmission response to peptide response to cytokine response to interleukin-1 neuromuscular junction development synaptic assembly at neuromuscular junction response to light stimulus visual learning visual behavior associative learning response to radiation response to abiotic stimulus dendrite development negative regulation of cell population proliferation cell population proliferation regulation of cell population proliferation intracellular calcium ion homeostasis smooth endoplasmic reticulum calcium ion homeostasis calcium ion homeostasis endoplasmic reticulum calcium ion homeostasis	somatodendritic compartment cell body cellular anatomical structure perikaryon neuronal cell body presynapse synapse cell junction presynaptic active zone cell-cell junction anchoring junction intracellular anatomical structure cytoplasm cytosol somatodendritic compartment cell body cellular anatomical structure perikaryon neuronal cell body presynapse synapse cell junction presynaptic active zone cell-cell junction anchoring junction intracellular anatomical structure cytoplasm cytosol membrane-bounded organelle intracellular organelle organelle endoplasmic reticulum smooth endoplasmic reticulum intracellular membrane-bounded organelle endomembrane system protein-containing complex receptor complex neuromuscular junction membrane-enclosed lumen intracellular organelle lumen endoplasmic reticulum lumen organelle lumen endosome intracellular vesicle recycling endosome cytoplasmic vesicle vesicle neuron spine neuron projection dendritic spine plasma membrane bounded cell projection cell projection postsynapse dendrite dendritic tree ciliary rootlet intracellular membraneless organelle cilium cytoskeleton membraneless organelle extracellular region extracellular space transport vesicle synaptic vesicle secretory vesicle exocytic vesicle mitochondrial membrane organelle inner membrane mitochondrion membrane mitochondrial inner membrane organelle envelope mitochondrial envelope organelle membrane cell surface cell periphery plasma membrane membrane microdomain membrane raft Golgi apparatus subcompartment Golgi apparatus organelle subcompartment trans-Golgi network membrane trans-Golgi network clathrin-coated pit apical part of cell spindle spindle midzone microtubule cytoskeleton extracellular exosome extracellular vesicle extracellular organelle extracellular membrane-bounded organelle COPII-coated ER to Golgi transport vesicle coated vesicle nucleus organelle envelope lumen nuclear envelope lumen nuclear envelope dendritic shaft perinuclear region of cytoplasm vesicle lumen cytoplasmic vesicle lumen secretory granule lumen secretory granule platelet alpha granule platelet alpha granule lumen axon Golgi-associated vesicle growth cone distal axon site of polarized growth early endosome Golgi lumen endosome lumen
A	TRYPSIN	peptidase activity catalytic activity, acting on a protein hydrolase activity catalytic activity endopeptidase activity serine hydrolase activity serine-type peptidase activity serine-type endopeptidase activity protein binding binding serpin family protein binding cation binding ion binding metal ion binding peptidase activity catalytic activity, acting on a protein hydrolase activity catalytic activity endopeptidase activity serine hydrolase activity serine-type peptidase activity serine-type endopeptidase activity protein binding binding serpin family protein binding cation binding ion binding metal ion binding small molecule binding	proteolysis metabolic process cellular process primary metabolic process protein metabolic process macromolecule metabolic process multicellular organismal process digestion	protein-containing complex serine protease inhibitor complex protease inhibitor complex peptidase inhibitor complex cellular anatomical structure extracellular region extracellular space

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
B	IPR013803	Amyloidogenic glycoprotein, amyloid-beta peptide	Domain
B	IPR008154	Amyloidogenic glycoprotein, extracellular	Domain
B	IPR036176	E2 domain superfamily	Homologous Superfamily
B	IPR024329	Amyloidogenic glycoprotein, E2 domain	Domain
B	IPR036669	Amyloidogenic glycoprotein, copper-binding domain superfamily	Homologous Superfamily
B	IPR019745	Amyloidogenic glycoprotein, intracellular domain, conserved site	Conserved Site
B	IPR011178	Amyloidogenic glycoprotein, copper-binding	Domain
B	IPR037071	Amyloidogenic glycoprotein, amyloid-beta peptide superfamily	Homologous Superfamily
B	IPR020901	Proteinase inhibitor I2, Kunitz, conserved site	Conserved Site
B	IPR019744	Amyloidogenic glycoprotein, copper-binding domain conserved site	Conserved Site
B	IPR002223	Pancreatic trypsin inhibitor Kunitz domain	Domain
B	IPR015849	Amyloidogenic glycoprotein, heparin-binding	Domain
B	IPR036454	Amyloidogenic glycoprotein, heparin-binding domain superfamily	Homologous Superfamily
B	IPR011993	PH-like domain superfamily	Homologous Superfamily
B	IPR019543	Beta-amyloid precursor protein C-terminal	Domain
B	IPR036880	Pancreatic trypsin inhibitor Kunitz domain superfamily	Homologous Superfamily
B	IPR008155	Amyloidogenic glycoprotein	Family
A	IPR009003	Peptidase S1, PA clan	Homologous Superfamily
A	IPR001314	Peptidase S1A, chymotrypsin family	Family
A	IPR033116	Serine proteases, trypsin family, serine active site	Active Site
A	IPR001254	Serine proteases, trypsin domain	Domain
A	IPR043504	Peptidase S1, PA clan, chymotrypsin-like fold	Homologous Superfamily
A	IPR050127	Serine Proteases (Peptidase S1 Family)	Family
A	IPR018114	Serine proteases, trypsin family, histidine active site	Active Site

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
B	Pharos: P05067	Alzheimer disease amyloidosis cerebral amyloid angiopathy dementia cerebral amyloid angiopathy, APP-related fragile X syndrome Down syndrome neurodegenerative disease Necrosis brain disease premature aging syndrome Alzheimer disease type 1 spinal cord disease dissociative amnesia amnestic disorder Alzheimer disease amyloidosis cerebral amyloid angiopathy dementia cerebral amyloid angiopathy, APP-related fragile X syndrome Down syndrome neurodegenerative disease Necrosis brain disease premature aging syndrome Alzheimer disease type 1 spinal cord disease dissociative amnesia amnestic disorder endogenous depression Gerstmann-Straussler-Scheinker syndrome osteosarcoma Huntington disease astrocytic tumor juvenile dermatomyositis ABeta amyloidosis, Arctic type Pick disease learning disability ABeta amyloidosis, Italian type Lewy body dementia prion disease cerebrovascular disorder malignant ependymoma amyotrophic lateral sclerosis ovarian cancer Parkinson disease atypical teratoid rhabdoid tumor large cell medulloblastoma ABeta amyloidosis, dutch type breast cancer ABetaL34V amyloidosis ACys amyloidosis psoriasis chronic obstructive pulmonary disease medulloblastoma depressive disorder Emery-Dreifuss muscular dystrophy FRAXE intellectual disability oligodendroglioma anxiety disorder head and neck cancer palsy periodic fever syndrome bipolar disorder ABeta amyloidosis, Iowa type polycystic ovary syndrome cardiomyopathy acquired metabolic disease lung carcinoma ADan amyloidosis rheumatoid arthritis dermatomyositis toxic encephalopathy