5U73

Crystal structure of human Niemann-Pick C1 protein

Replaces:  5I31

Summary for 5U73

• Entry DOI: 10.2210/pdb5u73/pdb
• Related: 5U74
• Descriptor: Niemann-Pick C1 protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (Human)
• Cellular location: Late endosome membrane ; Multi-pass membrane protein : O15118
• Total number of polymer chains: 1
• Total formula weight: 145622.01

Authors

Li, X.,Wang, J.,Blobel, G. (deposition date: 2016-12-11, release date: 2017-09-27, Last modification date: 2020-07-29)

Primary citation

Li, X.,Lu, F.,Trinh, M.N.,Schmiege, P.,Seemann, J.,Wang, J.,Blobel, G.
3.3 angstrom structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport.
Proc. Natl. Acad. Sci. U.S.A., 114:9116-9121, 2017

PubMed Abstract: Niemann-Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909-C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

PubMed: 28784760
DOI: 10.1073/pnas.1711716114

Experimental method

X-RAY DIFFRACTION (3.348 Å)