Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Roshan Javanshad; Thu T A Nguyen; Ruth D Azaria; Wenping Li; Daisy Edmison; Liang-Wei Gong; Swetha Gowrishankar; Andrew P Lieberman; Mark L Schultz; Stephanie M Cologna

doi:10.1021/acs.jproteome.3c00788

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Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Journal article

Peer reviewed

Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Roshan Javanshad, Thu T A Nguyen, Ruth D Azaria, Wenping Li, Daisy Edmison, Liang-Wei Gong, Swetha Gowrishankar, Andrew P Lieberman, Mark L Schultz and Stephanie M Cologna

Journal of proteome research, Vol.23(8), pp.3174-3187

08/02/2024

DOI: 10.1021/acs.jproteome.3c00788

PMCID: PMC12131329

PMID: 38686625

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Abstract

NPC intracellular cholesterol transporter 1 (NPC1) is a multipass, transmembrane glycoprotein mostly recognized for its key role in facilitating cholesterol efflux. Mutations in the NPC1 gene result in Niemann-Pick disease, type C (NPC), a fatal, lysosomal storage disease. Due to the progressively expanding implications of NPC1-related disorders, we investigated endogenous NPC1 protein–protein interactions in the mouse cortex and human-derived iPSCs neuronal models of the disease through coimmunoprecipitation-coupled with LC-MS based proteomics. The current study investigated protein–protein interactions specific to the wild-type and the most prevalent NPC1 mutation (NPC1I1061T) while filtering out any protein interactor identified in the Npc1–/– mouse model. Additionally, the results were matched across the two species to map the parallel interactome of wild-type and mutant NPC1I1061T. Most of the identified wild-type NPC1 interactors were related to cytoskeleton organization, synaptic vesicle activity, and translation. We found many putative NPC1 interactors not previously reported, including two SCAR/WAVE complex proteins that regulate ARP 2/3 complex actin nucleation and multiple membrane proteins important for neuronal activity at synapse. Moreover, we identified proteins important in trafficking specific to wild-type and mutant NPC1I1061T. Together, the findings are essential for a comprehensive understanding of NPC1 biological functions in addition to its classical role in sterol efflux.

Lysosomal Storage Disorder

Transmembrane Protein

Neurodegenerative Disease

Niemann-Pick type C

Interactome

Details

Title: Subtitle: Endogenous Protein-Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex
Creators: Roshan Javanshad - University of Illinois Chicago
Thu T A Nguyen - University of Illinois Chicago
Ruth D Azaria - University of Michigan
Wenping Li - University of Illinois Chicago
Daisy Edmison - University of Illinois Chicago
Liang-Wei Gong - University of Illinois Chicago
Swetha Gowrishankar - University of Illinois Chicago
Andrew P Lieberman - University of Michigan
Mark L Schultz - University of Iowa
Stephanie M Cologna - University of Illinois Chicago
Resource Type: Journal article
Publication Details: Journal of proteome research, Vol.23(8), pp.3174-3187
DOI: 10.1021/acs.jproteome.3c00788
PMID: 38686625
PMCID: PMC12131329
NLM abbreviation: J Proteome Res
eISSN: 1535-3907
Language: English
Electronic publication date: 04/30/2024
Date published: 08/02/2024
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
Record Identifier: 9984622887102771

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