Organization of transcriptional machinery by weak multivalent interactions

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Project Summary Weak multivalent interactions mediated by intrinsically disordered regions (IDRs) of proteins have been proposed to spatially organize the transcriptional machinery into multi-component clusters, yet we know little about how these IDRs interact with specific partners to enable functional outcomes. As these interactions are highly dynamic and cluster-dependent they have been overlooked by conventional strategies to identify protein-protein interactions. Our preliminary data support our overarching hypothesis that in the context of higher-order clusters weak multivalent interactions are capable of highly specific hetero-typic interactions leading to functional organization of the nucleus. Our long-term objective is to understand how weak multivalent interactions organize specific components of the transcriptional machinery in order to enable gene activation. The objective of the parent grant is to investigate the mechanism and function of cluster-mediated interactions of IDR of found on transcriptional coactivators. The proposed work in the diversity supplement focusses on investigating myocardin (MYOCD), a smooth muscle cell specific coactivator. The proposed work is directly related to Aim 3 of the parent grant, which proposes to investigate the functional role of coactivator IDRs in various models of gene activation including reporter assays and cell models of cellular differentiation. MYOCD is a smooth muscle cell specific coactivator, and we will be investigating the role of its IDR in reporter assays and smooth muscle cell differentiation. Completion of these studies will advance the goals and objectives of the parent grant and will teach us about how the function of prevalent yet often overlooked IDRs in gene activation.