Breann Brown, Ph.D.
Assistant Professor, Biochemistry
- : firstname.lastname@example.org
- : 615-343-1632
639C Light Hall
2215 Garland Avenue
Nashville, Tennessee - 37323
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Structural biology & protein assembly
Name: Breann Brown
Title: Assistant Professor of Biochemistry
Office Address: 639C Light Hall
Phone Number: 615-343-1632
Lab URL: https://lab.vanderbilt.edu/brown-lab
Research Keywords: X-ray crystallography, mitochondria, protein structure-function, heme, neurodegenerative diseases, structural biology, biophysics
Research Specialty: Structural biology of protein complexes regulating mitochondrial physiology
Macromolecular protein complex assembly is critical for maintaining human health. These precise interactions are necessary for modulating various cellular processes such as activity of signaling pathways, providing feedback regulation, and mediating transport and transfer of molecules among partners. Unfortunately, there are numerous painful, debilitating, and life-threatening diseases that occur due to genetic mutations that prevent proper protein assembly. Our approach is to use X-ray crystallography and other complementary biochemical techniques to understand how these various mutations lead to changes in protein structure and function, thus preventing productive macromolecular assembly. We focus on areas of human health related to mitochondrial biology and metabolism. Specifically, we seek to understand assembly mechanisms responsible for regulation of heme biosynthesis, which is altered in several blood diseases, and maintenance of mitochondrial DNA copy number, which has implications in proper neuronal development.
- Heme is an essential cofactor activating proteins critical in many biological processes, including energy production, gene regulation, and oxygen transport. Heme biosynthesis must be tightly controlled, as aberrant amounts can result in several blood diseases. The first and often rate-limiting step of heme biosynthesis, the condensation of glycine and succinyl-CoA yielding aminolevulinic acid (ALA), occurs in the mitochondrial matrix and is catalyzed by 5-aminolevulinic acid synthase (ALAS). Additionally, ALAS interacts with other proteins, such as the ATP-dependent unfoldase ClpX and the TCA cycle enzyme succinyl-CoA synthetase (SCS), to modulate its activity. Importantly, multiple mutations in the erythroid-specific isoform of human ALAS lead to loss of SCS binding, resulting in a decrease in ALAS activity and the disease X-linked sideroblastic anemia. We are interested in understanding the molecular basis for assembly of ALAS and SCS and how mutations in ALAS alter its structure to prevent binding to SCS.
- We are also interested in how protein assembly allows for proper neurological function. Nucleoside diphosphate kinase (NDPK) is a critical enzyme that helps maintain the mitochondrial dNTP pool. Interestingly, NDPK also interacts with SCS in order to maintain proper physiology. However, several genetic mutations in SCS, which in many cases leads to a loss of assembly with NDPK, result in severe neurological disorders. In this project, we are interested in answering several questions. How is NDPK activity and/or stability regulated by SCS? How does loss of protein assembly lead to depletion of mitochondrial DNA? And how does the key TCA cycle enzyme SCS play a role in such diverse processes?