Structural studies of NAC transcription factor ORE1 and schizophrenia risk gene AS3MT Pohang University of Science and Technology

Abstract

Chapter1. Abstract Aging and death are unavoidable fate of all organisms. Unlike animals, Plants use sophisticated mechanisms of gene expression to control senescence in response to environmental stress or aging. One of the representing plant aging is the leaf senescence. ORE1 (Arabidopsis thaliana NAC092) is a master regulator of senescence that belongs to the plant-specific NAC transcription factor protein family. ORE1 has been reported to bind to multiple DNA targets to orchestrate leaf senescence, yet the mechanistic basis for recognition of the cognate gene sequence remains unclear. Here, I present the crystal structure of the ORE1–NAC domain alone and its DNA-binding form. The structure of DNA-bound ORE1–NAC revealed the molecular basis for nucleobase recognition and phosphate backbone interactions. I show that local versatility in the DNA-binding site, in combination with domain flexibility of the ORE–NAC homodimer, is crucial for the maintenance of binding to intrinsically flexible DNA. My results provide a platform for understanding other plant-specific NAC protein– DNA interactions as well as insight into the structural basis of NAC regulators in plants of agronomic and scientific importance.

Chapter2. Abstract Schizophrenia is leading to a disruption of cognitive emotional, and social functions. This is mental disease depending on the level of social environment. However, the criteria of schizophrenia is vague. Because of schizophrenia’s molecular mechanisms is unclear and neurodevelopmental phenotypes are involved in pathology of schizophrenia. Recently, As3mt gene, coding Arsenite Methyltransferase, has been identified as a strong candidate gene for schizophrenia, by associating with genome-wide studies (GWAS). According to the GWAS study, novel isoform of AS3MT has been discovered, which is AS3MTd2d3, and its increased expression in brain samples of schizophrenia patients. Caused by alternative splicing, AS3MTd2d3 loses the enzymatic detoxification function and it appears in schizophrenia patient brain. Here is an identification of molecular mechanisms that affect the phenotype between AS3MTfull and AS3MTd2d3. When it goes isoform, AS3MTd2d3 goes dimerization itself. And I identified the key residue of dimerization. In addition, I have solved X-ray crystal structure of human AS3MTfull to understand human AS3MTd2d3 structure. My work demonstrates a potential molecular mechanism of AS3MT to understand difference between AS3MTfull and AS3MTd2d3.