Document text
Principal Investigator: Minglei Zhao
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $410,000
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY / ABSTRACT
Our lab focuses on structural and functional studies of molecular machines involved in chemical
modifications of macromolecules. Naturally occurring chemical modifications of macromolecules play essential
roles in all aspects of molecular biology, from transcriptional and translational regulation to functional modulation
of various proteins. Misregulation of the chemical modifications is involved in many human diseases such as
cancers and neurodegenerative diseases. Although many have been described and characterized, there are still
significant amounts of chemical modification systems that are poorly understood. Our long term goal is to
elucidate the structure and function of molecular machines involved in various chemical modification systems
and develop new tools and strategies to modulate their activity against the relevant diseases based on what we
have learned. In the next five years, we will be focusing on two systems, the p97 related ubiquitination system
and the Vault related ADP-ribosylation system.
More than thirty mutations of human p97 have been identified, which are associated with a number of
neurodegenerative diseases. The molecular mechanism, however, remains elusive. Through structural biology
approaches and protein engineering, we will address 1) how p97 processes ubiquitin chains of different
topologies through the cofactors; 2) the structural and functional consequences of disease mutations; 3) the
mechanism of inhibitors of p97 and its cofactors. Our efforts promise unprecedented insights into the function of
p97, a central hub of cellular protein homeostasis.
Vault is the largest ribonucleoprotein in eukaryotic cells with a unique structure. The function of Vault has
been linked to drug resistance in cancer and innate immune response. Recently, major vault protein (MVP) was
identified as one of the 9 marker genes that can predict influenza vaccination responses. Given the importance
of vaccine development during this COVID-19 pandemic, a deep understanding of Vault’s molecular mechanism
is critical. We are going to focus on PARP4, the only enzyme in the Vault complex catalyzing ADP-ribosylation.
Elucidating the function of PARP4 and how it interacts with Vault particle is the key to understand the molecular
function of Vault.
Terms: <ADP ribosylation><APF-1><ATP-Dependent Proteolysis Factor 1><Adopted><Biology><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cancers><Chemicals><Complex><DNA Molecular Biology><Degenerative Neurologic Disorders><Disease><Disorder><Drug resistance><Enzyme Gene><Enzymes><Eukaryotic Cell><Flu vaccination><Genetic Alteration><Genetic Change><Genetic Markers><Genetic defect><Goals><HMG-20><High Mobility Protein 20><Human><Influenza immunization><Influenza vaccination><Innate Immune Response><Learning><Link><Malignant Neoplasms><Malignant Tumor><Methods><Modern Man><Modification><Molecular><Molecular Biology><Molecular Machines><Mutation><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Play><Process><Prophylactic vaccination against influenza><Protein Engineering><Proteins><Ribonucleoproteins><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Structure><System><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Translational Regulation><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><cofactor><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><develop a vaccine><develop vaccines><development of a vaccine><drug resistant><flu immunisation><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><genetic protein engineering><genome mutation><human disease><influenza virus vaccination><inhibitor><insight><macromolecule><major vault protein><malignancy><neoplasm/cancer><neurodegenerative illness><particle><protein design><protein homeostasis><proteostasis><resistance to Drug><resistant to Drug><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><structural biology><tool><ubiquination><ubiquitin conjugation><vaccination against influenza><vaccine development>