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

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:

Rev1 inhibition enhances radioresistance and autophagy

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.
Authors
Ikeh, KE; Lamkin, EN; Crompton, A; Deutsch, J; Fisher, KJ; Gray, M; Argyle, DJ; Lim, WY; Korzhnev, DM; Kyle Hadden, M; Hong, J; Zhou, P; Chatterjee, N
MLA Citation
Ikeh, K. E., et al. “Rev1 inhibition enhances radioresistance and autophagy.” Cancers, vol. 13, no. 21, Nov. 2021. Scopus, doi:10.3390/cancers13215290.
URI
https://scholars.duke.edu/individual/pub1499235
Source
scopus
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13215290

Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the β3-β4 loop to favor a low-affinity drug-binding state.

Resistance to the extended-spectrum cephalosporin ceftriaxone in the pathogenic bacteria Neisseria gonorrhoeae is conferred by mutations in penicillin-binding protein 2 (PBP2), the lethal target of the antibiotic, but how these mutations exert their effect at the molecular level is unclear. Using solution NMR, X-ray crystallography, and isothermal titration calorimetry, we report that WT PBP2 exchanges dynamically between a low-affinity state with an extended β3-β4 loop conformation and a high-affinity state with an inward β3-β4 loop conformation. Histidine-514, which is located at the boundary of the β4 strand, plays an important role during the exchange between these two conformational states. We also find that mutations present in PBP2 from H041, a ceftriaxone-resistant strain of N. gonorrhoeae, increase resistance to ceftriaxone by destabilizing the inward β3-β4 loop conformation or stabilizing the extended β3-β4 loop conformation to favor the low-affinity drug-binding state. These observations reveal a unique mechanism for ceftriaxone resistance, whereby mutations in PBP2 lower the proportion of target molecules in the high-affinity drug-binding state and thus reduce inhibition at lower drug concentrations.
Authors
Fenton, BA; Tomberg, J; Sciandra, CA; Nicholas, RA; Davies, C; Zhou, P
MLA Citation
Fenton, Benjamin A., et al. “Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the β3-β4 loop to favor a low-affinity drug-binding state.J Biol Chem, vol. 297, no. 4, Oct. 2021, p. 101188. Pubmed, doi:10.1016/j.jbc.2021.101188.
URI
https://scholars.duke.edu/individual/pub1497421
PMID
34529975
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
297
Published Date
Start Page
101188
DOI
10.1016/j.jbc.2021.101188

Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B.

Photoactivated phytochrome B (PHYB) binds to antagonistically acting PHYTOCHROME-INTERACTING transcription FACTORs (PIFs) to regulate hundreds of light responsive genes in Arabidopsis by promoting PIF degradation. However, whether PHYB directly controls the transactivation activity of PIFs remains ambiguous. Here we show that the prototypic PIF, PIF3, possesses a p53-like transcription activation domain (AD) consisting of a hydrophobic activator motif flanked by acidic residues. A PIF3mAD mutant, in which the activator motif is replaced with alanines, fails to activate PIF3 target genes in Arabidopsis, validating the functions of the PIF3 AD in vivo. Intriguingly, the N-terminal photosensory module of PHYB binds immediately adjacent to the PIF3 AD to repress PIF3's transactivation activity, demonstrating a novel PHYB signaling mechanism through direct interference of the transactivation activity of PIF3. Our findings indicate that PHYB, likely also PHYA, controls the stability and activity of PIFs via structurally separable dual signaling mechanisms.
Authors
Yoo, CY; He, J; Sang, Q; Qiu, Y; Long, L; Kim, RJ-A; Chong, EG; Hahm, J; Morffy, N; Zhou, P; Strader, LC; Nagatani, A; Mo, B; Chen, X; Chen, M
MLA Citation
Yoo, Chan Yul, et al. “Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B.Nat Commun, vol. 12, no. 1, Sept. 2021, p. 5614. Pubmed, doi:10.1038/s41467-021-25909-5.
URI
https://scholars.duke.edu/individual/pub1497044
PMID
34556672
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
5614
DOI
10.1038/s41467-021-25909-5

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.
Authors
Adhikari, H; Kattan, WE; Kumar, S; Zhou, P; Hancock, JF; Counter, CM
MLA Citation
Adhikari, Hema, et al. “Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.Nat Commun, vol. 12, no. 1, Sept. 2021, p. 5248. Pubmed, doi:10.1038/s41467-021-25523-5.
URI
https://scholars.duke.edu/individual/pub1496179
PMID
34504076
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
5248
DOI
10.1038/s41467-021-25523-5

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.

All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
Authors
Lin, C-C; Ding, C-KC; Sun, T; Wu, J; Chen, K-Y; Zhou, P; Chi, J-T
MLA Citation
Lin, Chao-Chieh, et al. “The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.Cell Death Dis, vol. 12, no. 8, July 2021, p. 727. Pubmed, doi:10.1038/s41419-021-04018-7.
URI
https://scholars.duke.edu/individual/pub1488796
PMID
34294679
Source
pubmed
Published In
Cell Death & Disease
Volume
12
Published Date
Start Page
727
DOI
10.1038/s41419-021-04018-7