mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

Home

	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 PCSK9

Gene summary

Basic gene Info.	Gene symbol	PCSK9
	Gene name	proprotein convertase subtilisin/kexin type 9
	Synonyms	FH3\|HCHOLA3\|LDLCQ1\|NARC-1\|NARC1\|PC9
	Cytomap	UCSC genome browser: 1p32.3
	Type of gene	protein-coding
	RefGenes	NM_174936.3, NR_110451.1,
	Description	convertase subtilisin/kexin type 9 preproproteinneural apoptosis regulated convertase 1subtilisin/kexin-like protease PC9
	Modification date	20141222
dbXrefs	MIM : 607786
	HGNC : HGNC
	Ensembl : ENSG00000169174
	HPRD : 07080
	Vega : OTTHUMG00000008136
Protein	UniProt: Q8NBP7 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_PCSK9
	BioGPS: 255738
Pathway	NCI Pathway Interaction Database: PCSK9
	KEGG: PCSK9
	REACTOME: PCSK9
	Pathway Commons: PCSK9
Context	iHOP: PCSK9
	ligand binding site mutation search in PubMed: PCSK9
	UCL Cancer Institute: PCSK9
Assigned class in mutLBSgeneDB	A: This gene has a literature evidence and it belongs to targetable_mutLBSgenes.
References showing study about ligand binding site mutation for PCSK9.	1. Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., & Deisenhofer, J. (2008). Molecular basis for LDL receptor recognition by PCSK9. Proceedings of the National Academy of Sciences, 105(6), 1820-1825. 18250299

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

GO ID	GO Term	PubMed ID
GO:0001920	negative regulation of receptor recycling	17452316
GO:0002092	positive regulation of receptor internalization	17328821
GO:0007041	lysosomal transport	17452316
GO:0010469	regulation of receptor activity	17328821
GO:0010989	negative regulation of low-density lipoprotein particle clearance	17328821
GO:0016540	protein autoprocessing	14622975
GO:0032802	low-density lipoprotein particle receptor catabolic process	16912035

Top

Ligand binding site mutations for PCSK9

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
A330,A328	S329L	BLCA	1
D238	G236D	HNSC	1
D238	R237Q	SKCM	1
R194	E195K	SKCM	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.

Top

Protein structure related information for PCSK9

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
D238	R237Q	-1.6728657
R194	E195K	-0.62189177
D238	G236D	-0.50282651
A328	S329L	-0.08351285
A330	S329L	-0.08351285

(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 PCSK9 from PDB

Top

Differential gene expression and gene-gene network for PCSK9

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 PCSK9 and the right PPI network was created from samples without mutations in the LBS of PCSK9. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

Top

Phenotype information for PCSK9

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0020443	Hypercholesterolemia	49	Biomarker, GeneticVariation
umls:C1956346	Coronary Artery Disease	13	Biomarker, GeneticVariation
umls:C1863551	Hypercholesterolemia, Autosomal Dominant, 3	2	Biomarker, GeneticVariation

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

Top

Pharmacological information for PCSK9

Gene-centered drug-gene interaction network

Drug information targeting mutLBSgene (Approved drugs only)

Drug status	DrugBank ID	Name	Type	Drug structure
Approved	DB09302	Alirocumab	Biotech

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of PCSK9 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
CA		CALCIUM(2+)	2qtw	B	A328 A330
CA		CALCIUM(2+)	2w2m	A	A328 A330
CA		CALCIUM(2+)	2w2n	A	A328 A330
CA		CALCIUM(2+)	2w2q	A	A328 A330
CA		CALCIUM(2+)	3p5b	A	A328 A330
CA		CALCIUM(2+)	3p5c	A	A328 A330
CA		CALCIUM(2+)	2xtj	A	A330
III		Peptide ligand (ACE,THR,VAL,PHE,THR,SER,TRP,GLU,GLU,TYR,LEU,ASP,TRP,VAL,NH2)	4nmx	B	D238
III		Peptide ligand (GLY,THR,ASN,GLU,CYS,LEU,ASP,ASN,ASN,GLY,GLY,CYS,SER,HIS,VAL,CYS,ASN,ASP,LEU,LYS,ILE,GLY,TYR,GLU,CYS,LEU)	4ne9	B	R194 D238

Top

Conservation information for LBS of PCSK9

Multiple alignments for Q8NBP7 in multiple species

LBS	AA sequence	# species	Species
A239	VSGRDAGVAKG	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
A239	IGSKHFGVAKN	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
A239	IAGKTFGVSKN	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
A328	CLYSPASAPEV	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
A328	CLSSPAGAEKS	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
A328	CGTSPARVSNA	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
A330	YSPASAPEVIT	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
A330	SSPAGAEKSIT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
A330	TSPARVSNAMT	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
C358	TNFGRCVDLFA	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
C358	SNWGTCVDVFA	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
C358	SNIGSCVDIFA	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
C375	GASSDCSTCFV	3	Homo sapiens, Macaca mulatta, Pan troglodytes
C375	GASSDCSTCFM	1	Mus musculus
C375	GASSDCSTCYM	1	Rattus norvegicus
C375	STYIGSRNATL	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
C375	SDWIGSNRASM	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
C378	SDCSTCFVSQS	2	Homo sapiens, Pan troglodytes
C378	SDCSTCFVSRS	1	Macaca mulatta
C378	SDCSTCFMSQS	1	Mus musculus
C378	SDCSTCYMSQS	1	Rattus norvegicus
C378	IGSRNATLSLS	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
C378	IGSNRASMILS	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D238	VVSGRDAGVAK	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
D238	IIGSKHFGVAK	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D238	TIAGKTFGVSK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D360	FGRCVDLFAPG	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
D360	WGTCVDVFAPG	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D360	IGSCVDIFAPG	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
D374	IGASSDCSTCF	4	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus
D374	IGASSDCSTCY	1	Rattus norvegicus
D374	MSTYIGSRNAT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
D374	LSDWIGSNRAS	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
F379	DCSTCFVSQSG	2	Homo sapiens, Pan troglodytes
F379	DCSTCFVSRSG	1	Macaca mulatta
F379	DCSTCFMSQSG	1	Mus musculus
F379	DCSTCYMSQSG	1	Rattus norvegicus
F379	GSRNATLSLSG	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
F379	GSNRASMILSG	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
H557	CHQQGHVLTGC	3	Homo sapiens, Macaca mulatta, Pan troglodytes
H557	CHQKDHVLTGC	2	Mus musculus, Rattus norvegicus
H557	-----------	2	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
H602	HASCCHAPGLE	3	Homo sapiens, Macaca mulatta, Rattus norvegicus
H602	-----------	2	Saccharomyces cerevisiae (strain ATCC 204508 / S288c), Schizosaccharomyces pombe (strain 972 / ATCC 24843)
H602	HASCCRAPGLE	1	Pan troglodytes
H602	YASCCHAPGLE	1	Mus musculus
I369	PGEDIIGASSD	3	Homo sapiens, Macaca mulatta, Pan troglodytes
I369	PGKDIIGASSD	2	Mus musculus, Rattus norvegicus
I369	PGINIMSTYIG	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
I369	PGSLILSDWIG	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
I416	LRQRLIHFSAK	3	Homo sapiens, Macaca mulatta, Pan troglodytes
I416	LRQRLIHFSTK	1	Mus musculus
I416	LRQRLILFSTK	1	Rattus norvegicus
I416	LKEKVLKFSTQ	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
I416	LKKYMLKFALK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
K125	PGFLVKMSGDL	3	Homo sapiens, Macaca mulatta, Pan troglodytes
K125	PGFLVKMSSDL	2	Mus musculus, Rattus norvegicus
K125	RGYTGYFTDEI	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
K125	LGYAGRFSPWL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
L108	ARRGYLTKILH	3	Homo sapiens, Macaca mulatta, Pan troglodytes
L108	ARRGYVIKVLH	2	Mus musculus, Rattus norvegicus
L108	STSVGKLTEND	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
L108	EKRSLDFKDVS	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
L440	VLTPNLVAALP	3	Homo sapiens, Macaca mulatta, Pan troglodytes
L440	VLTPNLVATLP	1	Mus musculus
L440	VLTPNRVATLP	1	Rattus norvegicus
L440	--TPNKLI---	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
L440	--TPNVLA---	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
M126	GFLVKMSGDLL	3	Homo sapiens, Macaca mulatta, Pan troglodytes
M126	GFLVKMSSDLL	2	Mus musculus, Rattus norvegicus
M126	GYTGYFTDEII	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
M126	GYAGRFSPWLV	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
P155	-AQSIPWNLER	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
P155	LQEEAPWGLHR	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
P155	-QTFAPWGLAR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
P331	SPASAPEVITV	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
P331	SPAGAEKSITV	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
P331	SPARVSNAMTV	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
Q413	LAELRQRLIHF	4	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus
Q413	LAELRQRLILF	1	Rattus norvegicus
Q413	PQELKEKVLKF	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Q413	PVELKKYMLKF	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
R194	IQSDHREIEGR	3	Homo sapiens, Macaca mulatta, Pan troglodytes
R194	IQGAHREIEGR	1	Mus musculus
R194	IQSGHREIEGR	1	Rattus norvegicus
R194	IDTEHEDFEGR	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
R194	INIEHQDFQGR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
R412	TLAELRQRLIH	4	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus
R412	TLAELRQRLIL	1	Rattus norvegicus
R412	SPQELKEKVLK	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
R412	HPVELKKYMLK	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S153	---AQSIPWNL	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
S153	SSLQEEAPWGL	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
S153	E--QTFAPWGL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
S372	DIIGASSDCST	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
S372	NIMSTYIGSRN	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
S372	LILSDWIGSNR	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
T335	APEVITVGATN	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
T335	AEKSITVGAST	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
T335	VSNAMTVGAST	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
T377	SSDCSTCFVSQ	2	Homo sapiens, Pan troglodytes
T377	SSDCSTCFVSR	1	Macaca mulatta
T377	SSDCSTCFMSQ	1	Mus musculus
T377	SSDCSTCYMSQ	1	Rattus norvegicus
T377	YIGSRNATLSL	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
T377	WIGSNRASMIL	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
V333	ASAPEVITVGA	5	Homo sapiens, Macaca mulatta, Pan troglodytes, Mus musculus, Rattus norvegicus
V333	AGAEKSITVGA	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
V333	ARVSNAMTVGA	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)
V380	CSTCFVSQSGT	2	Homo sapiens, Pan troglodytes
V380	CSTCFVSRSGT	1	Macaca mulatta
V380	CSTCFMSQSGT	1	Mus musculus
V380	CSTCYMSQSGT	1	Rattus norvegicus
V380	SRNATLSLSGT	1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
V380	SNRASMILSGT	1	Schizosaccharomyces pombe (strain 972 / ATCC 24843)