Consequences of Non-physiological Ligands Binding to DREAM on Its Secondary and Tertiary Structures and Interactions with Intracellular Partners.

Authors

Samiol AzamFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Chemistry

First Advisor's Name

Jaroslava Miksovska

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Yesim Darici

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Yukching Tse-Dinh

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Yuan Liu

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Yi Xiao

Fifth Advisor's Committee Title

Committee member

Keywords

Lead neurotoxicity, cadmium neurotoxicity, neuronal calcium sensor, DREAM, lithium neuroprotection, presenelin, potassium channel, Alzheimer's disease

Date of Defense

11-12-2019

Abstract

Downstream regulatory antagonist modulator (DREAM) is 29 kDa neuronal calcium sensor (NCS) protein which is expressed in the hippocampus of the brain. DREAM is a multifunctional protein which is involved in a wide spectrum of biological processes, including regulation of potassium current in brain, modulation of pain, presenilin-1 processing, regulation of memory and learning. Exposure to toxic metals such as Pb2+ and Cd2+ have been associated with different types of neurodegenerative diseases. However, how these toxic metals induce neurotoxicity remains an active area of research. In this study, utilizing a combination of spectroscopic and calorimetric techniques, we demonstrated binding of these toxic metals to DREAM. We showed that Pb2+ and Cd2+ bind to EF-hands in DREAM and binding of these toxic metals alters DREAM secondary and tertiary structure. Pb2+ and Cd2+ association to DREAM also modulates DREAM interactions with FITC-labeled peptides that mimic binding sites of DREAM effector proteins, presenilin 1 and Kv channel in a similar way as Ca2+ binding. Considering the high sequence homology between DREAM and other NCS proteins, Pb2+ and Cd2+could bind to other NCS proteins and interactions of Pb2+ and Cd2+ to with NCS proteins could provide novel insight into the molecular mechanism of Pb2+ and Cd2+-induced neurotoxicity. Li+ has been used for the treatment of mental disorders for more than six decades. Increasing evidences from in vivo and in vitro studies have implicated that Li+ is a drug candidate for the treatment of neurogenerative diseases. However, the molecular mechanism through which Li+ exerts its therapeutic action has not elucidated yet. Here we investigated whether Li+ directly binds to DREAM and impact its structural and functional properties. We demonstrated that Li+ binding triggers structural rearrangement of DREAM and enhances DREAM interactions with site-1 and site-2 of the voltage-gated potassium channel. Results from this study suggest that DREAM and probably other NCS proteins are molecular targets of Li+ and binding of Li+ to DREAM could provide a novel insight into the molecular mechanism of Li+ therapeutic action.

Identifier

FIDC008837

Previously Published In

1. Azam, Samiol; Gessica St Louis; Miksovska, Jaroslava; (2019) Cadmium association to DREAM promotes DREAM interactions with intracellular partners in a similar manner as its physiological ligand, calcium. Metallomics; DOI: 10.1039/C9MT00059C.

2. Azam, Samiol; Miksovska, Jaroslava; (2019) Pb²⁺ binds to DREAM and modulates its interactions with binding partners: A link between neuronal calcium sensors and Pb²⁺ neurotoxicity. ACS Chemical Neuroscience; 10 (3), 1263–1272.

Recommended Citation

Azam, Samiol, "Consequences of Non-physiological Ligands Binding to DREAM on Its Secondary and Tertiary Structures and Interactions with Intracellular Partners." (2019). FIU Electronic Theses and Dissertations. 4325.
https://digitalcommons.fiu.edu/etd/4325