Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease

Proceedings of the National Academy of Sciences of the United States of America - Tập 100 Số 5 - Trang 2512-2517 - 2003
Natalia Friedland1, Heng-Ling Liou1, Peter Lobel1, Ann Stock1
1Center for Advanced Biotechnology and Medicine, Howard Hughes Medical Institute, Departments of Pharmacology and Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854

Tóm tắt

Niemann–Pick disease type C2 (NP-C2) is a fatal hereditary disease characterized by accumulation of low-density lipoprotein-derived cholesterol in lysosomes. Here we report the 1.7-Å resolution crystal structure of the cholesterol-binding protein deficient in this disease, NPC2, and the characterization of its ligand binding properties. Human NPC2 binds the cholesterol analog dehydroergosterol with submicromolar affinity at both acidic and neutral pH. NPC2 has an Ig-like fold stabilized by three disulfide bonds. The structure of the bovine protein reveals a loosely packed region penetrating from the surface into the hydrophobic core that forms adjacent small cavities with a total volume of ≈160 Å 3 . We propose that this region represents the incipient cholesterol-binding site that dilates to accommodate an ≈740-Å 3 cholesterol molecule.

Từ khóa


Tài liệu tham khảo

J L Goldstein, H H Hobbs, M S Brown The Metabolic and Molecular Bases of Inherited Disease, eds C R Scriver, A L Beaudet, W S Sly, D Valle (McGraw–Hill, New York) III, 2863–2913 (2001).

M C Patterson, M T Vanier, K Suzuki, J A Morris, E Carstea, E B Neufeld, J E Blanchette-Mackie, P G Pentchev The Metabolic and Molecular Bases of Inherited Disease, eds C R Scriver, A L Beaudet, W S Sly, D Valle (McGraw–Hill, New York) III, 3611–3633 (2001).

E D Carstea, J A Morris, K G Coleman, S K Loftus, D Zhang, C Cummings, J Gu, M A Rosenfeld, W J Pavan, D B Krizman, et al. Science 277, 228–231 (1997).

Y A Ioannou Nat Rev Mol Cell Biol 2, 657–668 (2001).

J P Davies, F W Chen, Y A Ioannou Science 290, 2295–2298 (2000).

S Naureckiene, D E Sleat, H Lackland, A Fensom, M T Vanier, R Wattiaux, M Jadot, P Lobel Science 290, 2298–2301 (2000).

C Kirchhoff, C Osterhoff, L Young Biol Reprod 54, 847–856 (1996).

N Okamura, S Kiuchi, M Tamba, T Kashima, S Hiramoto, T Baba, F Dacheux, J L Dacheux, Y Sugita, Y Z Jin Biochim Biophys Acta 1438, 377–387 (1999).

D C Ko, J Binkley, A Sidow, M P Scott Proc Natl Acad Sci USA 100, 2518–2525 (2003).

L B Larsen, P Ravn, A Boisen, L Berglund, T E Petersen Eur J Biochem 243, 437–441 (1997).

Z Otwinowski Proceedings of the CCP4 Study Weekend: Data Collection and Processing, eds L Sawyer, N Isaacs, S Bayley (Science and Engineering Research Council, Daresbury Laboratory, Warrington, U.K.), pp. 56–62 (1993).

A T Brünger, P D Adams, G M Clore, W L DeLano, P Gros, R W Grosse-Kunstleve, J S Jiang, J Kuszewski, M Nilges, N S Pannu, et al. Acta Crystallogr D 54, 905–921 (1998).

A Perrakis, R Morris, V S Lamzin Nat Struct Biol 6, 458–463 (1999).

T A Jones, J Y Zou, S W Cowan, M Kjeldgaard Acta Crystallogr A 47, 110–119 (1991).

F Schroeder, P Butko, G Nemecz, T J Scallen J Biol Chem 265, 151–157 (1990).

R P Bandwar, Y Jia, N M Stano, S S Patel Biochemistry 41, 3586–3595 (2002).

P J Kraulis J Appl Crystallogr 24, 946–950 (1991).

E A Merritt, D J Bacon Methods Enzymol 277, 505–524 (1997).

M B Lascombe, M Ponchet, P Venard, M L Milat, J P Blein, T Prange Acta Crystallogr D 58, 1442–1447 (2002).

J C Chen, L J Miercke, J Krucinski, J R Starr, G Saenz, X Wang, C A Spilburg, L G Lange, J L Ellsworth, R M Stroud Biochemistry 37, 5107–5117 (1998).

Q K Yue, I J Kass, N S Sampson, A Vrielink Biochemistry 38, 4277–4286 (1999).

Y Tsujishita, J H Hurley Nat Struct Biol 7, 408–414 (2000).

J F Glatz, J Storch Curr Opin Lipidol 12, 267–274 (2001).

M E Hodsdon, D P Cistola Biochemistry 36, 1450–1460 (1997).

J Liang, H Edelsbrunner, C Woodward Protein Sci 7, 1884–1897 (1998).

G Millat, K Chikh, S Naureckiene, D E Sleat, A H Fensom, K Higaki, M Elleder, P Lobel, M T Vanier Am J Hum Genet 69, 1013–1021 (2001).

H H Klünemann, M Elleder, W E Kaminski, K Snow, J M Peyser, J F O'Brien, D Munoz, G Schmitz, H E Klein, W W Pendlebury Ann Neurol 52, 743–749 (2002).

G A Mueller, D C Benjamin, G S Rule Biochemistry 37, 12707–12714 (1998).

S Ichikawa, H Hatanaka, T Yuuki, N Iwamoto, S Kojima, C Nishiyama, K Ogura, Y Okumura, F Inagaki J Biol Chem 273, 356–360 (1998).

U Derewenda, J Li, Z Derewenda, Z Dauter, G A Mueller, G S Rule, D C Benjamin J Mol Biol 318, 189–197 (2002).

C S Wright, S C Li, F Rastinejad J Mol Biol 304, 411–422 (2000).

N Inohara, G Nuñez Trends Biochem Sci 27, 219–221 (2002).

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 100 Số 5

2512-2517

Thông tin tác giả