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2.A.6.6.6
Liver/intestinal enterocyte brush border Niemann-Pick C1 like 1 (NPC1L1) protein; responsible for ezetimibe-sensitive absorption of luminal lipids and cholesterol via a transport mechanism (Altmann et al., 2004; Davies et al., 2005; Liscum, 2007, Dixit et al. 2007). NPC1L1-dependent sterol uptake seems to be a clathrin-mediated endocytic process and is regulated by cellular cholesterol content (Betters and Yu, 2010; Jia et al., 2011).  Dietary cholesterol induces trafficking of the intestinal NPC1L1 from the brush boarder to endosomes (Skov et al. 2011).  It distributes on the brush border membranes of enterocytes and the canalicular membranes of hepatocytes. It is the target of ezetimibe, a hypocholesterolemic drug which blocks internalization of NPC1L1 and cholesterol in the mouse small intestine (Wang and Song 2012; Xie et al. 2012). Human NPC1L1 is a 1,332-amino acid protein with a putative sterol-sensing domain (SSD) that shows sequence homology to HMG-CoA reductase (HMGCR), Niemann-Pick C1 (NPC1), and SREBP cleavage-activating protein (SCAP). NPC1L1 may have evolved at two sites (apical membrane of enterocytes and canalicular membrane of hepatocytes) to mediate cholesterol uptake through a clathrin-mediated endocytic process, protecting the body against fecal and biliary loss of cholesterol (Yu 2008).

Accession Number:Q9UHC9
Protein Name:Niemann-Pick C1-like protein 1
Length:1359
Molecular Weight:148698.00
Species:Homo sapeins [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Apical cell membrane1 / Multi-pass membrane protein2
Substrate lipids, cholesterol

Cross database links:

Genevestigator: Q9UHC9
eggNOG: prNOG19100
HEGENOM: HBG326129
RefSeq: NP_001095118.1    NP_037521.2   
Entrez Gene ID: 29881   
Pfam: PF02460   
Drugbank: Drugbank Link   
OMIM: 608010  gene+phenotype
KEGG: hsa:29881   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0030659 C:cytoplasmic vesicle membrane
GO:0016021 C:integral to membrane
GO:0008158 F:hedgehog receptor activity
GO:0006695 P:cholesterol biosynthetic process
GO:0030299 P:intestinal cholesterol absorption
GO:0042157 P:lipoprotein metabolic process

References (7)

[1] “Evidence for a Niemann-Pick C (NPC) gene family: identification and characterization of NPC1L1.”  Davies J.P.et.al.   10783261
[2] “Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption.”  Altmann S.W.et.al.   14976318
[3] “Human chromosome 7: DNA sequence and biology.”  Scherer S.W.et.al.   12690205
[4] “Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia.”  Davies J.P.et.al.   15671032
[5] “Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1.”  van der Veen J.N.et.al.   15604518
[6] “The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1).”  Garcia-Calvo M.et.al.   15928087
[7] “Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.”  Wang J.et.al.   15679830
Structure:
3QNT     

External Searches:

  • Search: DB with
  • BLAST ExPASy (Swiss Institute of Bioinformatics (SIB) BLAST)
  • CDD Search (Conserved Domain Database)
  • Search COGs (Clusters of Orthologous Groups of proteins)
  • 2° Structure (Network Protein Sequence Analysis)

Analyze:

Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MAEAGLRGWL LWALLLRLAQ SEPYTTIHQP GYCAFYDECG KNPELSGSLM TLSNVSCLSN 
61:	TPARKITGDH LILLQKICPR LYTGPNTQAC CSAKQLVSLE ASLSITKALL TRCPACSDNF 
121:	VNLHCHNTCS PNQSLFINVT RVAQLGAGQL PAVVAYEAFY QHSFAEQSYD SCSRVRVPAA 
181:	ATLAVGTMCG VYGSALCNAQ RWLNFQGDTG NGLAPLDITF HLLEPGQAVG SGIQPLNEGV 
241:	ARCNESQGDD VATCSCQDCA ASCPAIARPQ ALDSTFYLGQ MPGSLVLIII LCSVFAVVTI 
301:	LLVGFRVAPA RDKSKMVDPK KGTSLSDKLS FSTHTLLGQF FQGWGTWVAS WPLTILVLSV 
361:	IPVVALAAGL VFTELTTDPV ELWSAPNSQA RSEKAFHDQH FGPFFRTNQV ILTAPNRSSY 
421:	RYDSLLLGPK NFSGILDLDL LLELLELQER LRHLQVWSPE AQRNISLQDI CYAPLNPDNT 
481:	SLYDCCINSL LQYFQNNRTL LLLTANQTLM GQTSQVDWKD HFLYCANAPL TFKDGTALAL 
541:	SCMADYGAPV FPFLAIGGYK GKDYSEAEAL IMTFSLNNYP AGDPRLAQAK LWEEAFLEEM 
601:	RAFQRRMAGM FQVTFMAERS LEDEINRTTA EDLPIFATSY IVIFLYISLA LGSYSSWSRV 
661:	MVDSKATLGL GGVAVVLGAV MAAMGFFSYL GIRSSLVILQ VVPFLVLSVG ADNIFIFVLE 
721:	YQRLPRRPGE PREVHIGRAL GRVAPSMLLC SLSEAICFFL GALTPMPAVR TFALTSGLAV 
781:	ILDFLLQMSA FVALLSLDSK RQEASRLDVC CCVKPQELPP PGQGEGLLLG FFQKAYAPFL 
841:	LHWITRGVVL LLFLALFGVS LYSMCHISVG LDQELALPKD SYLLDYFLFL NRYFEVGAPV 
901:	YFVTTLGYNF SSEAGMNAIC SSAGCNNFSF TQKIQYATEF PEQSYLAIPA SSWVDDFIDW 
961:	LTPSSCCRLY ISGPNKDKFC PSTVNSLNCL KNCMSITMGS VRPSVEQFHK YLPWFLNDRP 
1021:	NIKCPKGGLA AYSTSVNLTS DGQVLDTVAI LSPRLEYSGT ISAHCNLYLL DSASRFMAYH 
1081:	KPLKNSQDYT EALRAARELA ANITADLRKV PGTDPAFEVF PYTITNVFYE QYLTILPEGL 
1141:	FMLSLCLVPT FAVSCLLLGL DLRSGLLNLL SIVMILVDTV GFMALWGISY NAVSLINLVS 
1201:	AVGMSVEFVS HITRSFAIST KPTWLERAKE ATISMGSAVF AGVAMTNLPG ILVLGLAKAQ 
1261:	LIQIFFFRLN LLITLLGLLH GLVFLPVILS YVGPDVNPAL ALEQKRAEEA VAAVMVASCP 
1321:	NHPSRVSTAD NIYVNHSFEG SIKGAGAISN FLPNNGRQF