[대학원 생명과학과 세미나 안내] 

연사 : David A. Agard 교수(University of California)

연제 : To fold or not to fold: the yin and yang of chaperone-mediated
client activation

일시 : 2019년 10월 1일 (화) 오후 2시

장소 : 하나과학관 A동 B122호

초청교수 : 우재성 교수

Abstract

The Hsp90 molecular chaperone is required for the function of a vast array of
signal transduction networks in eukaryotic cells. Unlike many other chaperones,
Hsp90s preferentially interact with near native states facilitating their folding and
remodeling for protein-protein and protein-ligand signaling. Our past work for the
mitochondrial Hsp90, TRAP1 revealed that the ATP hydrolysis is sequential and
deterministic, providing a unique opportunity to harness the energy of the first
ATP hydrolysis for client remodeling or cochaperone rearrangement, while the
second is used to progress through the chaperone cycle, releasing client and
cochaperones. We also discovered an unexpected mode of calcium regulation
specific to the mitochondrial orthologs.
By developing a complete reconstitution of the multi-chaperone machinery, we
have shown that the glucocorticoid receptor is inactivated by the Hsp70 system
and then reactivated by Hsp90. Careful coordination of the ATP cycles of the
chaperones and the transfer process is orchestrated via an
Hsp90:Hsp70:Hop:GR complex. Our on-going efforts in cryoEM are now
revealing the structure of the client loading complex and is beginning to elucidate
how the bound GR is distorted, inactivated, and re-activated.
We also determined the first atomic structure of an Hsp90:client complex-
Hsp90:Cdc37:Cdk4. This revealed that the kinase is pulled apart and threaded
through the lumen of a closed Hsp90, while Cdc37 wraps around the outside.
The previously uncharacterized Cdc37-N terminus formed a novel coiled-coil
structure that stabilizes kinase C-lobe:Hsp90 interactions via molecular mimickry.
We now have a structure of a similar complex using Her2, providing insights into
exactly what is conserved and client-specific differences. To be discussed are
insights into the molecular basis of client regulation and modulation by the Hsp90
machine resulting from these and other new cryoEM structures.