Disorder and Development

Prof. Keith Dunker, Indiana University School of Medicine, Indiana, USA

Tuesday 1st November
Cruciform Lecture Theatre 1
Time: 16:00

Intrinsically disordered proteins (IDPs) fail to form stable 3D structure on their own, existing instead as dynamic, interconverting conformational ensembles.  We have found evidence that IDPs are likely used in many developmental pathways.  Here we will discuss our model for the canonical Wnt pathway.  In this pathway, b-catenin is kept at low levels by means of the destruction complex, which contains Axin, APC, GSK3b (a kinase), CKIa (a kinase), and b-catenin (a kinase substrate). One major disorder-dependent role is that Axin’s long disordered segment contains localized binding regions for GSK-3β, β-catenin, and CKIα. By assembling these components onto one long, disordered, and flexible segment, Axin orchestrates their interactions. 

A second disorder-dependent role is that the disordered SAMP repeats of APC bind to the ordered RGS domain of Axin.  A third disorder-dependent role in our model is that there are no specific conformational changes by which the kinases are positioned next to their substrate; rather, everything occurs by random, stochastic motions of the disordered connectors. The fourth disorder-dependent role is that the disordered amino terminus of β-catenin provides all of the sites for phosphorylation. The fifth disorder-dependent role is that the same disordered region contains the lysines involved in β-catenin’s polyubiquitination. The sixth disorder-dependent role is that b-catenin’s disordered tail facilitates its entry via a narrow channel into the proteasome complex where b-catenin’s digestion occurs. Following the binding of the Wnt signaling protein to its receptor, the destruction complex disassembles, and b-catenin then accumulates, moves to the nucleus, and therein turns on many genes associated with various developmental processes.  Again, disorder plays important roles in the various steps up to and including gene regulation.  In summary, disorder appears to be crucial for development regulated by the Wnt pathway.  Similarly widespread involvement of disorder is observed for several other developmental pathways as well.

Keith's webpage: http://informatics.iupui.edu/people/keith-dunker/


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