Molecular Architecture of the Chick Vestibular Hair Bundle

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Abstract

Hair bundles of the inner ear have a unique structure and protein composition that underlies their sensitivity to mechanical stimulation. Using mass spectrometry, we identified and quantified >1100 proteins, present from a few to 400,000 copies per stereocilium, from purified chick bundles; 336 of these were significantly enriched in bundles. Bundle proteins that we detected have been shown to regulate cytoskeleton structure and dynamics, energy metabolism, phospholipid synthesis, and cell signaling. Three-dimensional imaging using electron tomography allowed us to count the number of actin-actin crosslinkers and actin-membrane connectors; these values compared well to those obtained from mass spectrometry. Network analysis revealed several hub proteins, including RDX (radixin) and SLC9A3R2 (NHERF2), which interact with many bundle proteins and may perform functions essential for bundle structure and function. The quantitative mass spectrometry of bundle proteins reported here establishes a framework for future characterization of dynamic processes that shape bundle structure and function.

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Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 27 December 2012

Publication date (Electronic): 20 January 2013

Publication date (Print): March 2013

Publication date PMC-release: 01 September 2013

Volume: 16

Issue: 3

Pages: 365-374

Affiliations

[1 ]Department of Neuroscience, University of Virginia, Charlottesville, VA 22908

[2 ]Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA

[3 ]Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

[4 ]W.M. Keck Biomedical Mass Spectrometry Lab, University of Virginia, Charlottesville, VA 22908

[5 ]Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA

[6 ]Department of Public Health & Preventive Medicine, Oregon Health & Science University, Portland, OR 97239, USA

[7 ]Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA

Author notes

[‡ ]Correspondence: gillespp@ 123456ohsu.edu

[*]

Co-first authors.

Article

Manuscript ID: NIHMS430496

DOI: 10.1038/nn.3312

PMC ID: 3581746

PubMed ID: 23334578

SO-VID: 8d304108-1722-4005-b198-ff8c9ca01b2a

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