4月18日计算科学报告--Intrinsically Disordered Proteins, Alternative Splicing, and Post-translational Modification (IDP-AS-PTM): A Toolkit for Developmental Biology
时间：2019-04-15
Speaker: Prof. Keith Dunker
Indiana University，USA
Location：Physics Building Room C313
Time: Thursday (Apr.18) 15:50-16:50
Title：Intrinsically Disordered Proteins, Alternative Splicing, and Post-translational Modification (IDP-AS-PTM): A Toolkit for Developmental Biology
Abstract:
Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both protein segments encoded by alternatively spliced pre-mRNA (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely G-protein coupled receptors (GPCRs), which are transmembrane signaling proteins, the nuclear factors of activated T-cells (NFATs), which are transcription factors (TFs), and the Src family kinases (SFKs), which are signaling enzymes. The goal here is to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or signaling proteins containing IDRs also undergo both AS- and PTM-based modifications, suggesting that these many proteins likely take advantage of signal outcome modulations that result from collaboration among these three features. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs substantially contributes to, or even provides the basis for, the vast complexity of eukaryotic cell signaling systems.
Biography：
In the 1980s to 1990s while at WSU Dr. Dunker was drawn to recognize the existence and importance of IDPs through three encounters with functional IDPs (Uversky's "Rule of Three"), especially Chuck Kissinger's November 15, 1995, Seminar on calcineurin (CaN). CaN is a serine-threonine phosphatase that contains a large auto-inhibitory IDR that shuts-off its own phosphatase activity in a manner that is reversed by calcium-calmodulin binding. This IDR is thus a calcium-dependent on-off switch for the phosphatase activity that connects calcium-based signaling with phosphate-based signaling, two of the most important signaling systems in eukaryotic cells. The truly spectacular functional importance of CaN’s IDR led Dr. Dunker to immediately switch his research focus, with the aid of Chuck Kissinger and computer scientist Zoran Obradovic and his student Pedro Romero, to computational studies on IDPs and IDRs. From this start in late 1995 until now, Dunker and co-workers have published over 300 papers on these topics, seehttps://scholar.google.com/citations?user=4agt6FcAAAAJ
