The lifecycle of HIV-1 is intimately associated with membranes. The virus particles have a membrane envelope that contains structural proteins responsible for recognition and fusion with susceptible cells, and the final step of viral reproduction involves the budding out of new virus particles from the membrane of infected cells. Vpu is a small (81 residue) HIV-1 accessory protein with two biological functions. It enhances the degradation of CD4/gp160 complexes, enabling gp160 to be processed to form the gp41 and gp120 proteins required for the formation of new virus particles, and it facilitates the budding out of new virus particles, perhaps through its ion channel activity. Structural biology is based on the premise that in order to understand how proteins express their biological functions it is essential to determine their three-dimensional structures. And this is certainly the case for Vpu where its biological activities appear to be associated with different regions of the protein structure. However, membrane proteins like Vpu present extraordinary technical challenges for structural biology, largely because the most widely used experimental methods were developed for soluble, globular proteins rather than hydrophobic proteins in lipid environments. The goal of the proposed research is to determine the three-dimensional structure of Vpu by using newly developed NMR experimental methods. This will bring Vpu into the realm of structural biology, and make it feasible to work towards the additional goals of understanding the molecular mechanisms for its biological activities and designing drugs that interfere with these activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM066978-01A1
Application #
6696791
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Wehrle, Janna P
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$266,000
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Berkamp, Sabrina; Park, Sang Ho; De Angelis, Anna A et al. (2017) Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy. J Biomol NMR 69:111-121
Opella, Stanley J; Marassi, Francesca M (2017) Applications of NMR to membrane proteins. Arch Biochem Biophys 628:92-101
Park, Sang Ho; Berkamp, Sabrina; Radoicic, Jasmina et al. (2017) Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR. Biophys J 113:2695-2705
Yao, Yong; Dutta, Samit Kumar; Park, Sang Ho et al. (2017) High resolution solid-state NMR spectroscopy of the Yersinia pestis outer membrane protein Ail in lipid membranes. J Biomol NMR 67:179-190
Das, Bibhuti B; Opella, Stanley J (2016) Simultaneous cross polarization to (13)C and (15)N with (1)H detection at 60kHz MAS solid-state NMR. J Magn Reson 262:20-26
Opella, Stanley J (2015) Solid-state NMR and membrane proteins. J Magn Reson 253:129-37
Das, Bibhuti B; Park, Sang Ho; Opella, Stanley J (2015) Membrane protein structure from rotational diffusion. Biochim Biophys Acta 1848:229-45
Opella, Stanley J (2015) Relating structure and function of viral membrane-spanning miniproteins. Curr Opin Virol 12:121-5
Lewinski, Mary K; Jafari, Moein; Zhang, Hua et al. (2015) Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly. J Biol Chem 290:10919-33
Park, Sang Ho; Wang, Vivian S; Radoicic, Jasmina et al. (2015) Paramagnetic relaxation enhancement of membrane proteins by incorporation of the metal-chelating unnatural amino acid 2-amino-3-(8-hydroxyquinolin-3-yl)propanoic acid (HQA). J Biomol NMR 61:185-96

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