PMID: 19563754

 

    Legend: Gene, Sites

Title : Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol

Abstract :

1. LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis
2. Exit of cholesterol from lysosomes requires two proteins , membrane-bound Niemann-Pick C1 ( NPC1 ) and soluble NPC2
3. NPC2 binds cholesterol with its isooctyl side chain buried and its 3beta-hydroxyl exposed
4. Here, we describe high-resolution structures of the N-terminal domain ( NTD ) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol
5. NPC1 ( NTD ) binds cholesterol in an orientation opposite to NPC2 : 3beta-hydroxyl buried and isooctyl side chain exposed
6. Cholesterol transfer from NPC2 to NPC1 ( NTD ) requires reorientation of a helical subdomain in NPC1 ( NTD ), enlarging the opening for cholesterol entry
7. NPC1 with point mutations in this subdomain (distinct from the binding subdomain ) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells
8. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2 , which transfers it to NPC1 ( NTD ), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes

Output (sent_index, trigger, protein, sugar, site):

Output(Part-Of) (sent_index, protein, site):

• 0. NPC1, domain
• 4. NPC1, domain

*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

Protein	NCBI ID	SENTENCE INDEX
NPC2	100770757	2,3,5,6,7,8
NPC1	100689424	0,2,4,5,6,7,8
NTD	100689424	4,5,6,8
Niemann-Pick C1	100689424	2