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SUMMARY:Role of Intrinsic Flexibility in Protein Regulatory Mechanisms - P
 rof. Richard Kriwacki\, St. Jude Children's Research Hospital\, Memphis\, 
 USA
DTSTART:20101007T151500Z
DTEND:20101007T160000Z
UID:TALK26023@talks.cam.ac.uk
CONTACT:Dr Madan Babu Mohan
DESCRIPTION:It is now widely recognized that intrinsically disordered prot
 eins (IDPs) occur in organisms from all kingdoms of life. In eukaryotes\, 
 >30% of genes encode IDPs which perform diverse biological functions\, man
 y involving regulation and signaling.  Despite increased awareness of IDPs
 \, the mechanisms that mediate their biological function(s) generally rema
 in poorly understood. How does disorder mediate the diverse functions of I
 DPs?  Studies of proteins that regulate cell division and apoptosis have p
 rovided answers.  The cell cycle regulators\, p21 and p27\, are prototypic
 al IDPs which fold upon binding to cyclin-dependent kinases (Cdks).  Disor
 der enables these proteins to promiscuously bind and regulate the entire f
 amily of Cdk/cyclin complexes which control cell division.  Further\, pers
 istent flexibility in the bound state allows p27 to integrate and transmit
  phosphorylation signals which ultimately drive cells into S phase—p27 s
 erves as a signaling conduit.  Studies of disordered proteins that regulat
 e apoptosis illustrate a different mechanism of signaling which controls t
 he pro-apoptotic activity of cytoplasmic p53.  The IDP\, PUMA\, mediates t
 he 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 seq
 uestered and inactivated by BCL-xL.  However\, while many BH3-only “de-r
 epressor” proteins can displace BID and BIM\, only PUMA can displace p53
  from BCL-xL\, triggering BAX activation and apoptosis.  We have discovere
 d that PUMA binding triggers dramatic structural rearrangement of BCL-xL w
 hich modulates its affinity for cytosolic p53\, providing a mechanistic mo
 del for PUMA-induced activation of p53-dependent apoptosis.  Importantly\,
  intrinsic flexibility of both disordered PUMA and globular BCL-xL is crit
 ical for this mechanism of signaling.  These contrasting examples illustra
 te mechanisms by which the flexibility of IDPs mediates signaling.  Howeve
 r\, given that thousands of disordered proteins perform myriad functions i
 n eukaryotic cells\, many more discoveries must be made to fully understan
 d the structural biology of IDPs. We will discuss our efforts to integrate
  results from structural\, biophysical\, biochemical and cellular investig
 ations to comprehensively understand disorder/function relationships for p
 roteins. 
LOCATION:Max Perutz Lecture Theatre\, MRC Laboratory of Molecular Biology\
 , Cambridge\, UK
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