mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

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	Gene Summary
	Ligand Binding Site Mutation Information
	Protein Structure Related Information
	Gene Expression and Gene-Gene Network
	Phenotype Information
	Pharmacological Information
	Conservation Information for LBS

Gene summary for CASP8

Gene summary

Basic gene Info.	Gene symbol	CASP8
	Gene name	caspase 8, apoptosis-related cysteine peptidase
	Synonyms	ALPS2B\|CAP4\|Casp-8\|FLICE\|MACH\|MCH5
	Cytomap	UCSC genome browser: 2q33-q34
	Type of gene	protein-coding
	RefGenes	NM_001080124.1, NM_001080125.1,NM_001228.4,NM_033355.3,NM_033356.3, NM_033358.3,NR_111983.1,NM_033357.2,
	Description	FADD-homologous ICE/CED-3-like proteaseFADD-like ICEICE-like apoptotic protease 5MACH-alpha-1/2/3 proteinMACH-beta-1/2/3/4 proteinMORT1-associated ced-3 homologapoptotic cysteine proteaseapoptotic protease Mch-5caspase 8, apoptosis-related cystein
	Modification date	20141221
dbXrefs	MIM : 601763
	HGNC : HGNC
	Ensembl : ENSG00000064012
	HPRD : 03459
	Vega : OTTHUMG00000132821
Protein	UniProt: Q14790 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_CASP8
	BioGPS: 841
Pathway	NCI Pathway Interaction Database: CASP8
	KEGG: CASP8
	REACTOME: CASP8
	Pathway Commons: CASP8
Context	iHOP: CASP8
	ligand binding site mutation search in PubMed: CASP8
	UCL Cancer Institute: CASP8
Assigned class in mutLBSgeneDB	B: This gene belongs to targetable_mutLBSgenes.

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez

GO ID	GO Term	PubMed ID
GO:0006508	proteolysis	12888622
GO:0036462	TRAIL-activated apoptotic signaling pathway	21785459
GO:0045862	positive regulation of proteolysis	18387192
GO:0097191	extrinsic apoptotic signaling pathway	21785459
GO:0097202	activation of cysteine-type endopeptidase activity	18387192

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Ligand binding site mutations for CASP8

Lollipop-style diagram of mutations at LBS in amino-acid sequence.
We represented ligand binding site mutations only. (You can see big image via clicking.)

: non-synonymous mutation on LBS, Circle size denotes number of samples.

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
S338	F340L	BLCA	1
S316	S316F	BRCA	1
Y324	G325D	COAD	1
V410	V410A	COAD	1
Y334	I333M	LUAD	1
S338	S338C	LUAD	1
C360	G362E	SKCM	1
E396	P394L	STAD	1
W420	W420C	UCEC	1

cf) Cancer type abbreviation. BLCA: Bladder urothelial carcinoma, BRCA: Breast invasive carcinoma, CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD: Colon adenocarcinoma, GBM: Glioblastoma multiforme, LGG: Brain lower grade glioma, HNSC: Head and neck squamous cell carcinoma, KICH: Kidney chromophobe, KIRC: Kidney renal clear cell carcinoma, KIRP: Kidney renal papillary cell carcinoma, LAML: Acute myeloid leukemia, LUAD: Lung adenocarcinoma, LUSC: Lung squamous cell carcinoma, OV: Ovarian serous cystadenocarcinoma, PAAD: Pancreatic adenocarcinoma, PRAD: Prostate adenocarcinoma, SKCM: Skin cutaneous melanoma, STAD: Stomach adenocarcinoma, THCA: Thyroid carcinoma, UCEC: Uterine corpus endometrial carcinoma.

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Protein structure related information for CASP8

Relative protein structure stability change (ΔΔE) using Mupro 1.1
Mupro score denotes assessment of the effect of mutations on thermodynamic stability.
(ΔΔE<0: mutation decreases stability, ΔΔE>0: mutation increases stability)

: nsSNV at non-LBS

: nsSNV at LBS

nsSNVs sorted by the relative stability change of protein structure by each mutation
Blue: mutations of positive stability change. and red : the most recurrent mutation for this gene.

LBS	AAchange of nsSNV	Relative stability change
V410	V410A	-1.4501218
S316	S316F	-1.277094
S338	F340L	-0.81135923
Y334	I333M	-0.79397724
Y324	G325D	-0.7280414
S338	S338C	-0.64239242
W420	W420C	-0.58025093
C360	G362E	-0.54995554
E396	P394L	-0.43413538

(MuPro1.1: Jianlin Cheng et al., Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines, PROTEINS: Structure, Function, and Bioinformatics. 2006, 62:1125-1132)

Structure image for CASP8 from PDB

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Differential gene expression and gene-gene network for CASP8

Differential gene expression between mutated and non-mutated LBS samples in all 16 major cancer types

Differential co-expressed gene network based on protein-protein interaction data (CePIN)

* Left PPI network was created from samples with mutations in the LBS of CASP8 and the right PPI network was created from samples without mutations in the LBS of CASP8. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

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Phenotype information for CASP8

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C2239176	Carcinoma, Hepatocellular	18	Biomarker, GeneticVariation
umls:C1458155	Breast Neoplasms	11	AlteredExpression, Biomarker, GeneticVariation
umls:C0025202	Melanoma	10	Biomarker, GeneticVariation
umls:C0007131	Carcinoma, Non-Small-Cell Lung	10	Biomarker
umls:C1168401	Carcinoma, squamous cell of head and neck	8	Biomarker, GeneticVariation
umls:C0024121	Lung Neoplasms	6	AlteredExpression, Biomarker, GeneticVariation
umls:C0001418	Adenocarcinoma	4	Biomarker, GeneticVariation
umls:C1328840	Autoimmune Lymphoproliferative Syndrome	4	Biomarker
umls:C1846545	CASPASE 8 DEFICIENCY	2	Biomarker, GeneticVariation
umls:C0038220	Status Epilepticus	2	Biomarker
umls:C0009404	Colorectal Neoplasms	2	Biomarker
umls:C0014859	Esophageal Neoplasms	2	Biomarker
umls:C0037286	Skin Neoplasms	1	Biomarker, GeneticVariation
umls:C2937358	Cerebral Hemorrhage	1	Biomarker
umls:C0162820	Dermatitis, Allergic Contact	1	Biomarker
umls:C0011860	Diabetes Mellitus, Type 2	1	Biomarker
umls:C0013604	Edema	1	Biomarker
umls:C0027055	Myocardial Reperfusion Injury	1	Biomarker
umls:C0950124	Papillomavirus Infections	1	Biomarker
umls:C0038356	Stomach Neoplasms	1	Biomarker
umls:C0007873	Uterine Cervical Neoplasms	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for CASP8

Gene expression profile of anticancer drug treated cell-lines (CCLE)
Heatmap showing the correlation between gene expression and drug response across all the cell-lines. We chose the top 20 among 138 drugs.We used Pearson's correlation coefficient.

Gene-centered drug-gene interaction network

Drug information targeting mutLBSgene (Approved drugs only)

Drug status

DrugBank ID

Name

Type

Drug structure

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of CASP8 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
III		Peptide ligand (ACE,ILE,GLU,THR,ASJ)	1qtn	A	C360
B93		(3S)-3-({[(5S)-2-{2-[(1H-BENZIMIDAZOL-5-YLCARBONYL)AMINO]ETHYL}-7-(CYCLOHEXYLMETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC ACID	3kjn	A	C360
B94		(3S)-3-({[(5S,8R)-2-(3-CARBOXYPROPYL)-8-(2-{[(4-CHLOROPHENYL)ACETYL]AMINO}ETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC ACID	3kjq	A	C360
B94		(3S)-3-({[(5S,8R)-2-(3-CARBOXYPROPYL)-8-(2-{[(4-CHLOROPHENYL)ACETYL]AMINO}ETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC ACID	3kjq	B	E396
III		Peptide ligand (ILE,GLU,THR,ASP)	2y1l	A	S316 C360
III		Peptide ligand (ILE,GLU,THR,ASP)	2y1l	C	S316 C360
III		Peptide ligand (ACE,1MH,ASP,B3L,HLX,1U8)	4jj7	A	S316 C360 V410
III		Peptide ligand (ACE,LEU,GLU,THR,1U8)	4prz	A	S316 C360 W420
III		Peptide ligand (BAL,LEU,GLN,PRO,1U8)	4ps1	A	S316 C360 W420
III		Peptide ligand (BAL,LEU,GLN,PRO,1U8)	4ps1	B	S316 C360 W420
III		Peptide ligand (BAL,LEU,GLN,PRO,1U8)	4ps1	C	S316 C360 W420
III		Peptide ligand (BAL,LEU,GLN,PRO,1U8)	4ps1	D	S316 C360 W420
III		Peptide ligand (PHQ,LEU,GLU,THR,MX5)	2c2z	A	S316 Y324 C360
III		Peptide ligand (ILE,GLU,THR,ASP)	2y1l	D	V410
III		Peptide ligand (ACE,ILE,GLU,THR,ASJ)	1qtn	B	V410 W420
III		Peptide ligand (ILE,GLU,THR,ASP)	2y1l	B	V410 W420
III		Peptide ligand (PHQ,LEU,GLU,THR,MX5)	2c2z	B	W420
B93		(3S)-3-({[(5S)-2-{2-[(1H-BENZIMIDAZOL-5-YLCARBONYL)AMINO]ETHYL}-7-(CYCLOHEXYLMETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC ACID	3kjn	B	W420
B94		(3S)-3-({[(5S,8R)-2-(3-CARBOXYPROPYL)-8-(2-{[(4-CHLOROPHENYL)ACETYL]AMINO}ETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC ACID	3kjq	A	Y334 S338

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Conservation information for LBS of CASP8

Multiple alignments for Q14790 in multiple species

LBS

AA sequence

# species

Species