Pei Zhou

Overview:

Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidating the dynamic behavior of proteins during the process of recognition. Recent advances in NMR techniques have enabled the study of significantly larger proteins and protein complexes. These innovations have also led to faster and more accurate structure determination. My research interests focus on the exploration of molecular recognition and conformation variability of protein complexes in crucial biomedical processes using state-of-the-art NMR techniques.

Positions:

Professor of Biochemistry

Biochemistry
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

Harvard University

Post-Doct Fellow, Biological Chemistry

Harvard University

Grants:

Structural Biology and Biophysics Training Program

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Biochemical and functional investigation of the novel enzymatic activities of MESH1

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Regulation of Germline Stem Cell Division in Drosophila

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

High sensitivity multi-purpose electron paramagnetic resonance spectroscopy for biotechnological and biomedical research

Administered By
Biochemistry
Awarded By
North Carolina Biotechnology Center
Role
Collaborating Investigator
Start Date
End Date

Discovery and validation of broadly effective LpxH inhibitors as novel therapeutics against multi-drug resistant Gram-negative pathogens

Administered By
Biochemistry
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

SARS-CoV-2 triggers DNA damage response in Vero E6 cells.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and general malaise may continue long after the infection has ended in recovered patients, suggesting that SARS-CoV-2 infection has profound consequences in the host cells. Here we report that SARS-CoV-2 infection can trigger a DNA damage response (DDR) in African green monkey kidney cells (Vero E6). We observed a transcriptional upregulation of the Ataxia telangiectasia and Rad3 related protein (ATR) in infected cells. In addition, we observed enhanced phosphorylation of CHK1, a downstream effector of the ATR DNA damage response, as well as H2AX. Strikingly, SARS-CoV-2 infection lowered the expression of TRF2 shelterin-protein complex, and reduced telomere lengths in infected Vero E6 cells. Thus, our observations suggest SARS-CoV-2 may have pathological consequences to host cells beyond evoking an immunopathogenic immune response.
Authors
Victor, J; Deutsch, J; Whitaker, A; Lamkin, EN; March, A; Zhou, P; Botten, JW; Chatterjee, N
MLA Citation
Victor, Joshua, et al. “SARS-CoV-2 triggers DNA damage response in Vero E6 cells.Biochem Biophys Res Commun, vol. 579, Nov. 2021, pp. 141–45. Pubmed, doi:10.1016/j.bbrc.2021.09.024.
URI
https://scholars.duke.edu/individual/pub1498750
PMID
34600299
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
579
Published Date
Start Page
141
End Page
145
DOI
10.1016/j.bbrc.2021.09.024

Degradation of Components of the Lpt Transenvelope Machinery Reveals LPS-Dependent Lpt Complex Stability in Escherichia coli.

Lipopolysaccharide (LPS) is a peculiar component of the outer membrane (OM) of many Gram-negative bacteria that renders these bacteria highly impermeable to many toxic molecules, including antibiotics. LPS is assembled at the OM by a dedicated intermembrane transport system, the Lpt (LPS transport) machinery, composed of seven essential proteins located in the inner membrane (IM) (LptB2CFG), periplasm (LptA), and OM (LptDE). Defects in LPS transport compromise LPS insertion and assembly at the OM and result in an overall modification of the cell envelope and its permeability barrier properties. LptA is a key component of the Lpt machine. It connects the IM and OM sub-complexes by interacting with the IM protein LptC and the OM protein LptD, thus enabling the LPS transport across the periplasm. Defects in Lpt system assembly result in LptA degradation whose stability can be considered a marker of an improperly assembled Lpt system. Indeed, LptA recruitment by its IM and OM docking sites requires correct maturation of the LptB2CFG and LptDE sub-complexes, respectively. These quality control checkpoints are crucial to avoid LPS mistargeting. To further dissect the requirements for the complete Lpt transenvelope bridge assembly, we explored the importance of LPS presence by blocking its synthesis using an inhibitor compound. Here, we found that the interruption of LPS synthesis results in the degradation of both LptA and LptD, suggesting that, in the absence of the LPS substrate, the stability of the Lpt complex is compromised. Under these conditions, DegP, a major chaperone-protease in Escherichia coli, is responsible for LptD but not LptA degradation. Importantly, LptD and LptA stability is not affected by stressors disturbing the integrity of LPS or peptidoglycan layers, further supporting the notion that the LPS substrate is fundamental to keeping the Lpt transenvelope complex assembled and that LptA and LptD play a major role in the stability of the Lpt system.
Authors
Martorana, AM; Moura, ECCM; Sperandeo, P; Di Vincenzo, F; Liang, X; Toone, E; Zhou, P; Polissi, A
MLA Citation
Martorana, Alessandra M., et al. “Degradation of Components of the Lpt Transenvelope Machinery Reveals LPS-Dependent Lpt Complex Stability in Escherichia coli.Front Mol Biosci, vol. 8, 2021, p. 758228. Pubmed, doi:10.3389/fmolb.2021.758228.
URI
https://scholars.duke.edu/individual/pub1506031
PMID
35004843
Source
pubmed
Published In
Frontiers in Molecular Biosciences
Volume
8
Published Date
Start Page
758228
DOI
10.3389/fmolb.2021.758228

Structural basis of NPR1 in activating plant immunity.

NPR1 is a master regulator of the defence transcriptome induced by the plant immune signal salicylic acid<sup>1-4</sup>. Despite the important role of NPR1 in plant immunity<sup>5-7</sup>, understanding of its regulatory mechanisms has been hindered by a lack of structural information. Here we report cryo-electron microscopy and crystal structures of Arabidopsis NPR1 and its complex with the transcription factor TGA3. Cryo-electron microscopy analysis reveals that NPR1 is a bird-shaped homodimer comprising a central Broad-complex, Tramtrack and Bric-à-brac (BTB) domain, a BTB and carboxyterminal Kelch helix bundle, four ankyrin repeats and a disordered salicylic-acid-binding domain. Crystal structure analysis reveals a unique zinc-finger motif in BTB for interacting with ankyrin repeats and mediating NPR1 oligomerization. We found that, after stimulation, salicylic-acid-induced folding and docking of the salicylic-acid-binding domain onto ankyrin repeats is required for the transcriptional cofactor activity of NPR1, providing a structural explanation for a direct role of salicylic acid in regulating NPR1-dependent gene expression. Moreover, our structure of the TGA3<sub>2</sub>-NPR1<sub>2</sub>-TGA3<sub>2</sub> complex, DNA-binding assay and genetic data show that dimeric NPR1 activates transcription by bridging two fatty-acid-bound TGA3 dimers to form an enhanceosome. The stepwise assembly of the NPR1-TGA complex suggests possible hetero-oligomeric complex formation with other transcription factors, revealing how NPR1 reprograms the defence transcriptome.
Authors
Kumar, S; Zavaliev, R; Wu, Q; Zhou, Y; Cheng, J; Dillard, L; Powers, J; Withers, J; Zhao, J; Guan, Z; Borgnia, MJ; Bartesaghi, A; Dong, X; Zhou, P
MLA Citation
Kumar, Shivesh, et al. “Structural basis of NPR1 in activating plant immunity.Nature, vol. 605, no. 7910, May 2022, pp. 561–66. Epmc, doi:10.1038/s41586-022-04699-w.
URI
https://scholars.duke.edu/individual/pub1520591
PMID
35545668
Source
epmc
Published In
Nature
Volume
605
Published Date
Start Page
561
End Page
566
DOI
10.1038/s41586-022-04699-w

SARS-CoV-2 hijacks host cell genome instability pathways.

The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorly defined. In this study, we report that SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection triggers host cell genome instability by modulating the expression of molecules of DNA repair and mutagenic translesion synthesis. Further, SARS-CoV-2 infection causes genetic alterations, such as increased mutagenesis, telomere dysregulation, and elevated microsatellite instability (MSI). The MSI phenotype was coupled to reduced MLH1, MSH6, and MSH2 in infected cells. Strikingly, pre-treatment of cells with the REV1-targeting translesion DNA synthesis inhibitor, JH-RE-06, suppresses SARS-CoV-2 proliferation and dramatically represses the SARS-CoV-2-dependent genome instability. Mechanistically, JH-RE-06 treatment induces autophagy, which we hypothesize limits SARS-CoV-2 proliferation and, therefore, the hijacking of host-cell genome instability pathways. These results have implications for understanding the pathobiological consequences of COVID-19.
Authors
Victor, J; Jordan, T; Lamkin, E; Ikeh, K; March, A; Frere, J; Crompton, A; Allen, L; Fanning, J; Lim, WY; Muoio, D; Fouquerel, E; Martindale, R; Dewitt, J; deLance, N; Taatjes, D; Dragon, J; Holcombe, R; Greenblatt, M; Kaminsky, D; Hong, J; Zhou, P; tenOever, B; Chatterjee, N
MLA Citation
Victor, Joshua, et al. “SARS-CoV-2 hijacks host cell genome instability pathways.Res Sq, Apr. 2022. Pubmed, doi:10.21203/rs.3.rs-1556634/v1.
URI
https://scholars.duke.edu/individual/pub1517880
PMID
35441168
Source
pubmed
Published In
Res Sq
Published Date
DOI
10.21203/rs.3.rs-1556634/v1

MESH1 knockdown triggers proliferation arrest through TAZ repression.

All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation and reprogram transcriptome. While mammalian genomes encode MESH1-the homolog of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumor sphere formation, and retarded xenograft growth. These antitumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed expression of TAZ, a HIPPO coactivator, and proliferative gene. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, reduced sphere formation, tumor growth inhibition, dNTP depletion, and transcriptional changes. Furthermore, TAZ repression was associated with the histone hypo-acetylation at TAZ regulatory loci due to the induction of epigenetic repressors HDAC5 and AHRR. Together, MESH1 knockdown in human cells altered the genome-wide transcriptional patterns and arrested proliferation that mimicked the bacterial stringent response through the epigenetic repression of TAZ expression.
Authors
Sun, T; Ding, C-KC; Zhang, Y; Zhang, Y; Lin, C-C; Wu, J; Setayeshpour, Y; Coggins, S; Shepard, C; Macias, E; Kim, B; Zhou, P; Gordân, R; Chi, J-T
MLA Citation
Sun, Tianai, et al. “MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell Death Dis, vol. 13, no. 3, Mar. 2022, p. 221. Pubmed, doi:10.1038/s41419-022-04663-6.
URI
https://scholars.duke.edu/individual/pub1512788
PMID
35273140
Source
pubmed
Published In
Cell Death & Disease
Volume
13
Published Date
Start Page
221
DOI
10.1038/s41419-022-04663-6