Abstract:
:Export of LDL-derived cholesterol from lysosomes requires the cooperation of the integral membrane protein Niemann-Pick C1 (NPC1) and a soluble protein, Niemann-Pick C2 (NPC2). Mutations in the genes encoding these proteins lead to Niemann-Pick disease type C (NPC). NPC2 binds to NPC1's second (middle), lumenally oriented domain (MLD) and transfers cholesterol to NPC1's N-terminal domain (NTD). Here, we report the 2.4-Å resolution crystal structure of a complex of human NPC1-MLD and NPC2 bearing bound cholesterol-3-O-sulfate. NPC1-MLD uses two protruding loops to bind NPC2, analogous to its interaction with the primed Ebola virus glycoprotein. Docking of the NPC1-NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and NTD cholesterol binding pockets, supporting the "hydrophobic hand-off" cholesterol transfer model.
journal_name
Proc Natl Acad Sci U S Aauthors
Li X,Saha P,Li J,Blobel G,Pfeffer SRdoi
10.1073/pnas.1611956113subject
Has Abstractpub_date
2016-09-06 00:00:00pages
10079-84issue
36eissn
0027-8424issn
1091-6490pii
1611956113journal_volume
113pub_type
杂志文章abstract::We have developed an efficient, versatile, and user-friendly viral engineering and expression system that is based on in planta assembly of functional viral vectors from separate pro-vector modules. With this new system, instead of supplying a plant cell with a complete viral vector as a mature viral particle, an RNA ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0400149101
更新日期:2004-05-04 00:00:00
abstract::Residues important in the interaction between the 23-residue transmembrane (TM) domains of the integrin alpha(IIb)- and beta(3)-subunits were identified by mutating each non-Leu residue to Leu. Leu substitutions of alpha(IIb) at G972, G976, and T981, and of beta(3) at I693 and G708, increased ligand binding. Substitut...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0409440102
更新日期:2005-03-08 00:00:00
abstract::Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidas...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1313029110
更新日期:2013-11-12 00:00:00
abstract::Using an expression cloning approach, we have isolated a cDNA encoding GD3 synthase (CMP-NeuAc:NeuAc alpha 2-3Gal beta 1-4Glc beta 1-1'Cer alpha 2,8-sialyltransferase, EC 2.4.99.8), which is a key regulatory enzyme determining the prominence of the ganglioside biosynthesis pathway. The cloned cDNA encodes a 341-amino ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.91.17.7952
更新日期:1994-08-16 00:00:00
abstract::The tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/β-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/β-catenin signaling in mouse s...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1802422115
更新日期:2018-08-07 00:00:00
abstract::The term quantum turbulence denotes the turbulent motion of quantum fluids, systems such as superfluid helium and atomic Bose-Einstein condensates, which are characterized by quantized vorticity, superfluidity, and, at finite temperatures, two-fluid behavior. This article introduces their basic properties, describes t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type:
doi:10.1073/pnas.1400033111
更新日期:2014-03-25 00:00:00
abstract::The high frequency, recent origin, and geographic distribution of the CCR5-Delta 32 deletion allele together indicate that it has been intensely selected in Europe. Although the allele confers resistance against HIV-1, HIV has not existed in the human population long enough to account for this selective pressure. The ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2435085100
更新日期:2003-12-09 00:00:00
abstract::Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stai...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.11.6469
更新日期:1998-05-26 00:00:00
abstract::A proton NMR method is described for determining the orientation of a porphyrin within the heme pocket of a hemoprotein. The pattern of the hyperfine-shifted heme methyl resonances in low-spin ferric model compounds is demonstrated to characteristically reflect the position of a localized low-symmetry perturbation on ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.75.12.5755
更新日期:1978-12-01 00:00:00
abstract::Phenylglyoxal is an arginine-specific reagent that inactivates creatine kinase (CK). Previous results suggest that modification of the dimeric enzyme at a single arginine residue per subunit causes complete inactivation accompanied by the loss of nucleotide binding; the actual site of modification was not identified. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.7.3362
更新日期:1998-03-31 00:00:00
abstract::There has been an increasing interest in cyanobacteria because these photosynthetic organisms convert solar energy into biomass and because of their potential for the production of biofuels. However, the exploitation of cyanobacteria for bioengineering requires knowledge of their transcriptional organization. Using di...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1015154108
更新日期:2011-02-01 00:00:00
abstract::Three-dimensional microfluidic systems were fabricated and used to pattern proteins and mammalian cells on a planar substrate. The three-dimensional topology of the microfluidic network in the stamp makes this technique a versatile one with which to pattern multiple types of proteins and cells in complex, discontinuou...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.040562297
更新日期:2000-03-14 00:00:00
abstract::Isolation and chromatography of collagen from chick cartilage revealed an excess of alpha1 relative to alpha2-chains. Characterization of the cyanogen bromide peptides from the alpha1 fraction indicated the presence of two homologous forms of alpha1. The results suggest that cartilage contains two collagens, one ident...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.64.4.1264
更新日期:1969-12-01 00:00:00
abstract::The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ERalpha and ERbeta. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type an...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.96.26.15133
更新日期:1999-12-21 00:00:00
abstract::The infectious reovirus RNA system was used to construct a mutant with two temperature-sensitive (ts) lesions in genome segments M2 and S2, respectively. The double mutant is about 300 times more ts than either of its parents, which are about 1,500 and 170 times more ts than their wild-type parent reovirus ST3 strain ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.13.6826
更新日期:1997-06-24 00:00:00
abstract::Based largely on studies in xenograft models, lipocalin-2 (Lcn2) has been implicated in the progression of multiple types of human tumors, including breast cancer. Here we examine the role of Lcn2 in mammary tumorigenesis and lung metastasis using an in vivo molecular genetics approach. We crossed a well-characterized...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1000101107
更新日期:2010-02-16 00:00:00
abstract::Genotype-phenotype relationships are notoriously complicated. Idiosyncratic interactions between specific combinations of mutations occur and are difficult to predict. Yet it is increasingly clear that many interactions can be understood in terms of global epistasis. That is, mutations may act additively on some under...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1804015115
更新日期:2018-08-07 00:00:00
abstract::Burkitt's lymphomas, linked by previous studies with the DNA-containing Epstein-Barr virus, contain an RNA related in sequence to that of Rauscher leukemia virus. The present study establishes that the viral-related RNA found in Burkitt's tumors is a 70S component encapsulated with RNA-instructed DNA polymerase in a p...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.70.3.737
更新日期:1973-03-01 00:00:00
abstract::A library of Photobacterium phosphoreum DNA was screened in lambda 2001 for the lumazine protein gene, using two degenerate 17-mer oligonucleotide probes that were deduced from a partial protein primary sequence. The lumazine protein gene was localized to a 3.4-kilobase BamHI/EcoRI fragment in one clone. The fragment ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.4.1100
更新日期:1991-02-15 00:00:00
abstract::Although many types of ancient bacteria and archea rely on hydrogen sulfide (H(2)S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H(2)S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to co...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1115634109
更新日期:2012-02-21 00:00:00
abstract::Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0509937103
更新日期:2006-07-25 00:00:00
abstract::Analogy-the ability to find and apply deep structural patterns across domains-has been fundamental to human innovation in science and technology. Today there is a growing opportunity to accelerate innovation by moving analogy out of a single person's mind and distributing it across many information processors, both hu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1807185116
更新日期:2019-02-05 00:00:00
abstract::The leukemic fusion gene AML1-MDS1-EVI1 (AME) encodes a chimeric transcription factor that results from the t(3,21)(q26;q22) translocation seen in patients with acute myeloid leukemia, with therapy-related myelodysplastic syndrome, or with chronic myeloid leukemia in blast crisis. The myeloid transcription factor CEBP...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0404731101
更新日期:2004-09-07 00:00:00
abstract::Translocation of proteins across the mitochondrial inner membrane is an essential process requiring an import motor having mitochondrial Hsp70 (mtHsp70) at its core. The J protein partner of mtHsp70, Pam18, is an integral part of this motor, serving to stimulate the ATPase activity of mtHsp70. Pam16, an essential prot...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0505969102
更新日期:2005-08-30 00:00:00
abstract::Somatic-cell hybrids have been shown to maintain the correct epigenetic chromatin states to study developmental globin gene expression as well as gene expression on the active and inactive X chromosomes. This suggests the potential use of somatic-cell hybrids containing either a maternal or a paternal human chromosome...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.25.14857
更新日期:1998-12-08 00:00:00
abstract::MicroRNAs (miRNAs) are small, 18-22 nt long, noncoding RNAs that act as potent negative gene regulators in a variety of physiological and pathological processes. To repress gene expression, miRNAs are packaged into RNA-induced silencing complexes (RISCs) that target mRNAs for degradation and/or translational repressio...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1408037111
更新日期:2014-07-01 00:00:00
abstract::Existing moral psychology research commonly explains certain phenomena in terms of a motivation to blame. However, this motivation is not measured directly, but rather is inferred from other measures, such as participants' judgments of an agent's blameworthiness. The present paper introduces new methods for assessing ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1501592112
更新日期:2015-03-24 00:00:00
abstract::The induction of antigen-specific tolerance is critical for the prevention of autoimmunity and maintenance of immune tolerance. In addition to their classical role as sentinels of the immune response-inducing T cell reactivity, dendritic cells (DCs) play an important role in maintaining peripheral tolerance through th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0504484102
更新日期:2005-09-20 00:00:00
abstract::The GTPase-activating protein (GAP) has been postulated to function either as a negative regulator or as a possible target protein of Ras in mammalian cells and Xenopus oocytes. Ras must be localized in the plasma membrane of vertebrate cells to function, but GAP is localized in the cytosol. To test whether Ras functi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.17.6630
更新日期:1989-09-01 00:00:00
abstract::DNA and protein determinants of nucleosome positioning have been examined after in vitro reconstitutions of native or modified histone octamers onto tandem repeats of 207- and 172-base-pair DNA sequences containing the Lytechinus variegatus 5S rRNA gene and onto monomeric sequences derived from these by digestion with...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.87.15.5724
更新日期:1990-08-01 00:00:00