This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tyrosine phosphorylation is an important signal that tightly regulates many cellular responses mediated by the immune system. Protein tyrosine phosphatases (PTP) antagonize these key signal transduction pathways though their intrinsic dephosphorylation activity. Intracellular pathogens, such as Mycobacterium tuberculosis (Mtb), may secrete PTPs to evade host responses or achieve immune escape. The catalytic mechanisms, cellular functions and host substrates of the two Mtb PTPs (PtpA and PtpB) are largely unknown. I will investigate PtpB?s autoinhibitory lid, a structural feature that blocks potential substrates as well as reactive oxygen species (ROS) access to the protein?s active site. I will structurally characterize the conformational changes that occur when the lid opens, how oxidation affects the open and closed forms of the protein, and protein bound to inhibitors that may block mycobacterial infection and persistence. These studies will provide a greater mechanistic understanding of Mtb PTPs and their role in interfering with host signaling. The protein constructs used in these studies will include wild-type, wild-type oxidized, lid opening mutants, lid opening mutants-oxidized, and deleted lid protein with and without inhibitor.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-30
Application #
7954317
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2009-03-01
Project End
2010-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
30
Fiscal Year
2009
Total Cost
$213
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Vickers, Chelsea; Liu, Feng; Abe, Kento et al. (2018) Endo-fucoidan hydrolases from glycoside hydrolase family 107 (GH107) display structural and mechanistic similarities to ?-l-fucosidases from GH29. J Biol Chem 293:18296-18308
Nguyen, Phong T; Lai, Jeffrey Y; Lee, Allen T et al. (2018) Noncanonical role for the binding protein in substrate uptake by the MetNI methionine ATP Binding Cassette (ABC) transporter. Proc Natl Acad Sci U S A 115:E10596-E10604
Aleman, Fernando; Tzarum, Netanel; Kong, Leopold et al. (2018) Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors. Proc Natl Acad Sci U S A 115:7569-7574
Herrera, Nadia; Maksaev, Grigory; Haswell, Elizabeth S et al. (2018) Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance. Sci Rep 8:14566
Lal, Neeraj K; Nagalakshmi, Ugrappa; Hurlburt, Nicholas K et al. (2018) The Receptor-like Cytoplasmic Kinase BIK1 Localizes to the Nucleus and Regulates Defense Hormone Expression during Plant Innate Immunity. Cell Host Microbe 23:485-497.e5
Pluvinage, Benjamin; Grondin, Julie M; Amundsen, Carolyn et al. (2018) Molecular basis of an agarose metabolic pathway acquired by a human intestinal symbiont. Nat Commun 9:1043
Beyerlein, Kenneth R; J├Ânsson, H Olof; Alonso-Mori, Roberto et al. (2018) Ultrafast nonthermal heating of water initiated by an X-ray Free-Electron Laser. Proc Natl Acad Sci U S A 115:5652-5657
Yoshizawa, Takuya; Ali, Rustam; Jiou, Jenny et al. (2018) Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Cell 173:693-705.e22
Noach, Ilit; Ficko-Blean, Elizabeth; Pluvinage, Benjamin et al. (2017) Recognition of protein-linked glycans as a determinant of peptidase activity. Proc Natl Acad Sci U S A 114:E679-E688
Robb, Melissa; Hobbs, Joanne K; Woodiga, Shireen A et al. (2017) Molecular Characterization of N-glycan Degradation and Transport in Streptococcus pneumoniae and Its Contribution to Virulence. PLoS Pathog 13:e1006090

Showing the most recent 10 out of 604 publications