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Clues to NPC1-Mediated Cholesterol Export from Lysosomes

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Clues to NPC1-Mediated Cholesterol Export from Lysosomes COMMENTARY Clues to NPC1-mediated cholesterol export from lysosomes COMMENTARY Suzanne R. Pfeffera,1 Cholesterol is an essential component of cellular mem- branes and an important precursor for the generation of other biomolecules. Cholesterol is carried in the plasma in esterified form by low-density lipoprotein particles. Low-density lipoprotein is recognized by cell surface receptors that internalize the particles and deliver them to the lysosome, where cholesterol esters are hydro- lyzed and cholesterol is then delivered to the cytoplasm for storage or reuse (1). Although cholesterol is capable of freely partitioning in and out of most cellular mem- branes, it cannot be exported from lysosomes without the help of two proteins, Neimann–Pick C1 (NPC1) and NPC2 (2). Native NPC1 is a 1,254-aa-long, multipass membrane glycoprotein located in the limiting mem- brane of lysosomes; NPC2 is a smaller, 151-residue pro- tein, present in the lysosome lumen. In addition to its important role in cholesterol transport, NPC1 has also been identified as a key component required for the entry of Ebola virus into the cytoplasm (3, 4). In PNAS Li et al. (5) present a 3D structural model of NPC1, which Fig. 1. Structural models for NPC1 [PDB ID code 3JD8 (20)] and NPC1* [PDB ID provides important new clues to the mechanisms by code 5I31 (5)] by cryo-EM and X-ray crystallography, respectively. Lumenal which cholesterol is exported from lysosomes and the domains are colored as indicated (red, N-terminal domain; blue, lumenal mechanism by which Ebola virus docks on the internal domain 2; yellow, lumenal domain 3). P691 is indicated in magenta; NPC2 with bound cholesterol sulfate (PDB ID code 2HKA) is shown above. Note that the surface of the lysosome-limiting membrane as part of transmembrane helices were modeled as poly-alanine sequences in the cryo- the infection process. EM structure and are less accurate than those in the crystal structure. NPC1 and NPC2 proteins were discovered through Occupancy of the proposed sterol binding site is indicated by a red cholesterol analysis of the genes responsible for Niemann–Pick molecule. type C (NPC) disease (6, 7). NPC1 contains 13 transmem- brane domains and three, relatively large lumenally ori- How does NPC1 export cholesterol from lysosomes? ented domains (8) (Fig. 1). Of note is the presence of a Infante et al. discovered that NPC1’s N-terminal domain so-called sterol-sensing domain in transmembrane do- binds cholesterol and this capacity is required for lyso- main sequences that is also present in important sterol- somal cholesterol export (10, 11). The N-terminal do- regulated proteins, such as HMGCR (hydroxymethylglutaryl main binds cholesterol in opposite orientation from CoA reductase), Patched, and SCAP (sterol regulatory NPC2, suggesting the possibility of a direct hand-off element-binding protein cleavage-activating protein). of cholesterol from a soluble NPC2 protein to mem- Ninety-five percent of patients with NPC disease are ho- brane-associated NPC1 (12). Although this model is mozygous carriers of mutations in the NPC1 protein, and disease-causing mutations can be found across the very attractive, a direct interaction between the NPC1 length of the entire protein. Mutant NPC1 cells show mas- N-terminal domain and NPC2 protein has not been de- sive accumulation of cholesterol and glycosphingolipids tected to date. Using an engineered, soluble construct, in late endosomes and lysosomes. NPC2 is a cholesterol Deffieu and Pfeffer (13) showed that NPC1’ssecond binding protein that binds cholesterol via its iso-octyl lumenal domain binds NPC2 directly, but only at the moiety (9) (Fig. 1). low pH seen in endosomes and lysosomes and only aDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305-5307 Author contributions: S.R.P. conceived ideas presented, synthesized previous literature, and wrote the paper. The author declares no conflict of interest. See companion article on page 8212. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1608530113 PNAS | July 19, 2016 | vol. 113 | no. 29 | 7941–7943 Downloaded by guest on September 23, 2021 when it carries cholesterol (13). Thus, the second domain of NPC1 sterol-sensing domains of SCAP and HMGCR that is important might hold onto NPC2 to facilitate cholesterol transfer from NPC2 to for interactions with the protein, Insig, is both conserved in the NPC1 N-terminal domain. This second lumenal domain was later NPC1 and oriented in such a way that it is available for interaction shown to represent a critical binding partner for Ebola virus (14). with other protein partners within the membrane bilayer. Hints that NPC1’s sterol-sensing domain might also bind ste- What about the missing N-terminal domain and the first rols came from earlier studies that showed direct cross-linking of transmembrane span? A slightly lower resolution structure of the cholesterol to the NPC1 protein in cells harboring wild-type but full-length NPC1 protein structure was recently reported by Nieng not a sterol-sensing domain, P691-mutant form (15). Moreover, Yan and her colleagues using single-particle cryo-electron micros- analysis of small molecules that function as pharmacological chap- copy (cryo-EM) (20) (Fig. 1). In that study, the N-terminal domain erones also implicated the existence of a second sterol-binding site (16); the recent finding that non–N-terminal domain sequences Li et al. present a 3D structural model of NPC1, provide a binding site for the small, sterol-like molecule, U18666A (17), further supports the notion that NPC1 contains at least two which provides important new clues to the sterol-binding sites. mechanisms by which cholesterol is exported The ability to generate soluble versions of both the NPC1 N-terminal from lysosomes and the mechanism by which domain and a lumenal domain 2, facilitated structure determination Ebola virus docks on the internal surface of the for these domains (12, 18, 19). Missing, however, was an understand- ing of how these domains fit together and how the transmembrane lysosome-limiting membrane. domains are oriented. The challenge of obtaining crystals of large, multipass membrane proteins has been aided recently by better pro- lies directly on top of the remainder of NPC1 in 45% of selected tein-expression systems, special detergents, and other novel technol- particles, after 2D classification (Fig. 1). The observation that not ogies. Courage is also required, and the fearlessness of Li et al. (5) all NPC1 molecules are capped by the N-terminal domain is made it possible to obtain a structure model of most of the NPC1 consistent with a model in which the N-terminal domain interacts protein with a resolution of 3.6 Å. These authors used a Baculovirus- reversibly with the rest of NPC1, by virtue of the poly-proline derived system to infect human cells and then isolated NPC1 after tether that connects it to the rest of the protein. The capped form membrane solubilization in dodecylmaltoside plus cholesteryl may represent an inactive state of NPC1 protein because surface hemisuccinate. NPC1’s N-terminal domain is attached to the remain- residues needed for interaction with NPC2 (and Ebola virus) are der of the protein by a poly-proline–containing flexible arm (12). This shielded by the presence of the N-terminal domain. Nevertheless, flexibility seems to have precluded crystallization of the full-length both the N-terminal domain and lumenal domain 2 are likely to protein. Nevertheless, proteolysis yielded a clean NPC1* protein interface with NPC2 as part of the cholesterol transfer process (residues 314–1278) that includes 12 of the 13 transmembrane domains (12, 13, 20). Both the cryo-EM and crystal structures highlight and two lumenal domains, and was successfully crystallized (Fig. 1). the unusual height of the protein in relation to the lysosome’s The NPC1 structure revealed that the transmembrane helices internal limiting membrane (5, 20). This height may serve to bundle in an oblong manner, reminiscent of bacterial resistance- provide a cholesterol transfer mechanism that can enable cho- nodulation-cell division (RND) transporters. Sequence homology to lesterol to be passed through the glycocalyx that lines the these transporters was long appreciated, but seemed to be re- limiting membrane. stricted to the transmembrane domains, and thus was considered an Taken together, these data suggest that NPC2 picks up choles- anomaly more than an important clue. The structure model of the terol from endocytosed cholesterol, as well as from the significant nonmembrane portions, in the context of NPC1*, shows more ho- lipid content present in the lumen of degradative lysosomes. NPC2 mology to RND transporters than expected, and reveals that the would then interact with NPC1 via its second lumenal domain, in intertwined, lumenal domains 2 and 3 are structurally related, de- a manner that enables it to transfer bound cholesterol to the spite a significant difference in their disulfide bond content. N-terminal domain (Fig. 1). Because NPC2 binds NPC1 more Importantly, Li et al. (5) discovered a possible, hydrophobic tightly when it is carrying cholesterol (13), NPC2 would be re- sterol binding pocket, formed by transmembrane helices 3–5, that leased after cholesterol transfer. The next step might involve is located right at the boundary between the protein and the transfer of cholesterol from the N-terminal domain to NPC1’s lumenal membrane surface; an unusual feature of this site is that membrane-embedded, sterol-binding pocket. An important ques- cholesterol can access it from inside the lysosome and then diffuse tion is whether the poly-proline linker that appears to be ∼40 Å in laterally into the plane of the bilayer. This pocket is also predicted length by cryo-EM (20) can provide sufficient flexibility and length to be able to accommodate U18666A, the small-molecule NPC1 to accomplish intramolecular transfer.
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