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Role of Intrinsic Flexibility in Protein Regulatory Mechanisms

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If you have a question about this talk, please contact Dr Madan Babu Mohan.

It is now widely recognized that intrinsically disordered proteins (IDPs) occur in organisms from all kingdoms of life. In eukaryotes, >30% of genes encode IDPs which perform diverse biological functions, many involving regulation and signaling. Despite increased awareness of IDPs, the mechanisms that mediate their biological function(s) generally remain poorly understood. How does disorder mediate the diverse functions of IDPs? Studies of proteins that regulate cell division and apoptosis have provided answers. The cell cycle regulators, p21 and p27, are prototypical IDPs which fold upon binding to cyclin-dependent kinases (Cdks). Disorder enables these proteins to promiscuously bind and regulate the entire family of Cdk/cyclin complexes which control cell division. Further, persistent flexibility in the bound state allows p27 to integrate and transmit phosphorylation signals which ultimately drive cells into S phase—p27 serves as a signaling conduit. Studies of disordered proteins that regulate apoptosis illustrate a different mechanism of signaling which controls the pro-apoptotic activity of cytoplasmic p53. The IDP , PUMA, mediates the pro-apoptotic activity of a diverse set of cytosolic proteins termed “direct activators”, including the BH3 -only proteins, BID and BIM , and the tumor suppressor, p53. Like BID and BIM , cytoplasmic p53 is sequestered and inactivated by BCL -xL. However, while many BH3 -only “de-repressor” proteins can displace BID and BIM , only PUMA can displace p53 from BCL -xL, triggering BAX activation and apoptosis. We have discovered that PUMA binding triggers dramatic structural rearrangement of BCL -xL which modulates its affinity for cytosolic p53, providing a mechanistic model for PUMA -induced activation of p53-dependent apoptosis. Importantly, intrinsic flexibility of both disordered PUMA and globular BCL -xL is critical for this mechanism of signaling. These contrasting examples illustrate mechanisms by which the flexibility of IDPs mediates signaling. However, given that thousands of disordered proteins perform myriad functions in eukaryotic cells, many more discoveries must be made to fully understand the structural biology of IDPs. We will discuss our efforts to integrate results from structural, biophysical, biochemical and cellular investigations to comprehensively understand disorder/function relationships for proteins.

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