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Grant support

Ara Parseghian Medical Research Foundation Suzanne R Pfeffer; National Institutes of Health 5R01HL134991-04 Suzanne R Pfeffer; Chan Zuckerberg BioHub Joshua E Elias; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Analysis of institutional authors

Lu López, AlbertAuthor
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Article

Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins

Publicated to:Elife. 9 (e57089): - 2020-05-15 9(e57089), DOI: 10.7554/eLife.57089

Authors: Saha, P; Shumate, JL; Caldwell, JG; Elghobashi-Meinhardt, N; Lu, A; Zhang, LC; Olsson, NE; Elias, JE; Pfeffer, SR

Affiliations

Calico Life Sci LLC, San Francisco, CA USA - Author
Chan Zuckerberg BioHub, Stanford, CA USA - Author
Merck Res Labs, San Francisco, CA USA - Author
Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA - Author
Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA - Author
Tech Univ Berlin, Dept Chem, Berlin, Germany - Author
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Abstract

Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Either introducing single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes transport activity by both NPC1 and NPC1L1. The widely prescribed cholesterol uptake inhibitor, ezetimibe, blocks NPC1L1; we show that residues that lie at the interface between NPC1L1's three extracellular domains comprise the drug's binding site. These data support a model in which cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various domains is needed for transfer and ezetimibe blocks transport by binding to multiple domains simultaneously.

Keywords
biochemistrycell biologychemical biologycholesterol transportezetimibehumanldl cholesterollysosomeAbsorption inhibitorDeficientEzetimibe-sensitive cholesterolN-terminal domainNiemann pick c diseasePick c1 proteinPotentRequiresRolesSterol binding

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Elife due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 5/93, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 4.27, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-16, the following number of citations:

  • WoS: 11
  • Scopus: 27
  • Google Scholar: 30
  • OpenCitations: 29
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-16:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 60.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 60 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 11.9.
  • The number of mentions on the social network X (formerly Twitter): 21 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; United States of America.