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DisARdered, but Abl to Function: Elucidating the Interactions Governing the Intrinsically Disordered Complex Formed between the Androgen Receptor (AR) and Abl Interactor 1 (ABI1)
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Bah, Alaji
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Summer 2025
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2025-07-23
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Intrinsically disordered proteins (IDPs) are proteins that do not have a fixed three-dimensional structure. IDPs can be fully unstructured, or contain modular regions of folded structure and unstructure, known as intrinsically disordered regions (IDRs). IDPs/IDRs are dynamic, fluctuating through diverse conformational ensembles that allow them to play widespread roles in biological functions, both during normal and pathological conditions. IDPs/IDRs play a pivotal role in a multitude of cellular processes including, but not limited to, proliferation, migration, differentiation, and apoptosis. Here, I will focus on Abl kinase Interactor 1 (ABI1), a modular scaffolding protein, whose biophysical investigation had remained elusive for decades.
ABI1 is a multi-isoform and modular adaptor and scaffolding protein that plays a critical role in the organization of the cytoskeleton via downstream coordination of actin cytoskeletal reorganization with growth and proliferation signals as member of the WAVE complex. ABI1 also controls the progression of prostate tumors and acts as a prostate tumor suppressor wherein loss of ABI1 contributes to tumor metastasis. It is now known that ABI1 also functions in the nucleus, binding to DNA and nuclear hormone receptors (NHRs) like the androgen receptor (AR). My overall goal is to investigate the molecular basis of ABI1's functions. Through biophysical methods, I will study the intra- and intermolecular interactions between ABI1 and AR. Due to their difficulty in expression and purification, there is little in vitro data on the biophysical and structural mechanisms underlying the interaction between ABI1 and AR.
The results obtained will elucidate how the DNA-ABI1-AR axis regulates transcription, and will set the stage for developing novel inhibitors for prostate cancer. Without this knowledge, our understanding of ABI1's functions in regulating AR in normal and prostate cancer will remain limited. This work will have a positive impact by providing a model for determining the mechanism of the interactions of ABI1 and other nuclear hormone receptors, such as the estrogen receptor, a major driver of breast cancer.
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