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Niemann-Pick C1-like protein 1 (NPC1L1)
Function:
1) role in cholesterol homeostasis
2) role in uptake of cholesterol across plasma membrane of intestinal enterocyte
3) role in transport of multiple lipids
4) role in regulating lipid metabolism & homeostasis
Structure:
- belongs to the patched family
- contains 1 SSD (sterol-sensing) domain
- highly glycosylated
Compartment:
- apical cell membrane
- cytoplasmic vesicle membrane fraction, rich in RAB5
Alternative splicing: named isoforms=3
Expression:
- widely expressed
- expressed in liver, small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach, muscle
- downregulated in Caco-2 cells upon PPARD activation
Pathology:
- lack of activity leads to multiple lipid transport defects
Pharmacology:
- ezetimibe, a drug that inhibits cholesterol absorbtion, directly inhibits NPC1L1
Polymorphism:
- variations in NPC1L1 gene could be associated with response to ezetimibe treatment
- variations in NPC1L1 that inhibit its function that lower plasma LDL cholesterol levels & a reduce the risk of coronary artery disease [2]
General
carrier protein (transporter)
glycoprotein
transmembrane 13 protein
Properties
SIZE: MW = 149 kD
entity length = 1359 aa
COMPARTMENT: cytoplasm
MOTIF: exoplasmic domain {1-284}
MOTIF: signal sequence {1-21}
N-glycosylation site {N54}
N-glycosylation site {N132}
N-glycosylation site {N138}
N-glycosylation site {N244}
transmembrane domain {285-305}
cytoplasmic loop {306-351}
transmembrane domain {352-372}
exoplasmic loop {373-632}
MOTIF: N-glycosylation site {N416}
N-glycosylation site {N431}
N-glycosylation site {N464}
N-glycosylation site {N479}
N-glycosylation site {N497}
N-glycosylation site {N506}
N-glycosylation site {N626}
transmembrane domain {633-653}
cytoplasmic loop {654-666}
transmembrane domain {667-687}
exoplasmic loop {688-696}
transmembrane domain {697-717}
cytoplasmic loop {718-742}
transmembrane domain {743-763}
exoplasmic loop {764-776}
transmembrane domain {777-797}
cytoplasmic loop {798-846}
transmembrane domain {847-867}
exoplasmic loop {868-882}
transmembrane domain {883-903}
cytoplasmic loop {904-1139}
transmembrane domain {1140-1160}
exoplasmic loop {1161-1168}
transmembrane domain {1169-1189}
cytoplasmic loop {1190-1191}
transmembrane domain {1192-1212}
exoplasmic loop {1213-1236}
transmembrane domain {1237-1257}
cytoplasmic domain {1258-1359}
Database Correlations
OMIM 608010
MORBIDMAP 608010
UniProt Q9UHC9
Pfam PF02460
References
- UniProt :accession Q9UHC9
- The Myocardial Infarction Genetics Consortium Investigators
Inactivating Mutations in NPC1L1 and Protection from Coronary
Heart Disease.
N Engl J Med. Nov 12, 2014
PMID: 25390462
http://www.nejm.org/doi/full/10.1056/NEJMoa1405386