Caveolae are highly-curved invaginated micro-domains located in the plasma membrane that play a central role in a variety of cellular processes. Caveolins (1, 2, and 3) are the most important proteins found in caveolae, and are responsible for giving caveolae their unusual """"""""flask-like"""""""" shape. Recent evidence has shown that improper regulation and mutant forms of caveolin can result in a variety of diseases including Alzheimer's, muscular dystrophy, cancer, and heart disease. Caveolin adopts an unusual intra-membrane """"""""horseshoe"""""""" conformation where both its N- and C-termini face the cytoplasm, and this conformation is thought to promote membrane curvature. In addition, via high-order oligomerization, caveolin forms a structural backbone which stabilizes the membrane curvature. Using biophysical techniques such as nuclear magnetic resonance (NMR), fluorescence spectroscopy, and analytical ultracentrifugation, our objective is to characterize caveolin-1 on a fundamental level. This will be achieved by pursuing the following two specific aims: 1. Investigation of the membrane topology and three-dimensional structure of caveolin-1. 2. Investigation of caveolin-1 oligomerization.
Specific aim 1 will determine the high-resolution three-dimensional solution structure of caveolin-1 as well as examine the solvent accessibility of tryptophan residues to assess the topology of caveolin-1 in a bilayer. Next, the role that two conserved proline residues play in the creation and/or stabilization of the intra-membrane """"""""horseshoe"""""""" conformation will be probed using site-directed mutagenesis.
Specific aim 2 will characterize both the size and distribution of oligomers formed by caveolin-1 in the presence and absence of cholesterol. Additionally, the role that a proline to leucine mutant plays in the oligomerization process will be probed. A fundamental understanding of caveolin-1 structure and oligomerization will undoubtedly open the door to possible therapeutic interventions that could address diseases linked to caveolin misfunction.

Public Health Relevance

Caveolins are proteins that play an important role in a variety of events that happen within the cell. Alterations in the behavior of caveolins have been implicated in a variety of diseases including Alzheimer's, muscular dystrophy, cancer, and heart disease. Therefore, a more complete understanding of caveolins is necessary.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Chin, Jean
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Lehigh University
Schools of Arts and Sciences
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Plucinsky, Sarah M; Root, Kyle T; Glover, Kerney Jebrell (2018) Efficient solubilization and purification of highly insoluble membrane proteins expressed as inclusion bodies using perfluorooctanoic acid. Protein Expr Purif 143:34-37
Mukai, Masaru; Glover, Kerney Jebrell; Regen, Steven L (2016) Evidence for Surface Recognition by a Cholesterol-Recognition Peptide. Biophys J 110:2577-80
Root, Kyle T; Glover, Kerney Jebrell (2016) Reconstitution and spectroscopic analysis of caveolin-1 residues 62-178 reveals that proline 110 governs its structure and solvent exposure. Biochim Biophys Acta 1858:682-8
Plucinsky, Sarah M; Glover, Kerney Jebrell (2015) Secondary Structure Analysis of a Functional Construct of Caveolin-1 Reveals a Long C-Terminal Helix. Biophys J 109:1686-8
Rui, Huan; Root, Kyle T; Lee, Jinwoo et al. (2014) Probing the U-shaped conformation of caveolin-1 in a bilayer. Biophys J 106:1371-80
Rieth, Monica D; Lee, Jinwoo; Glover, Kerney Jebrell (2012) Probing the caveolin-1 P132L mutant: critical insights into its oligomeric behavior and structure. Biochemistry 51:3911-8
Lee, Jinwoo; Glover, Kerney Jebrell (2012) The transmembrane domain of caveolin-1 exhibits a helix-break-helix structure. Biochim Biophys Acta 1818:1158-64