Daniel C. Masison, Ph.D. : NIDDK

Daniel C. Masison, Ph.D.


LBG
GENETICS OF SIMPLE EUKARYOTES SECTION
NIDDK, National Institutes of Health
Building 8, Room 225
8 Center Dr.
Bethesda, MD 20892-0830
Tel: 301-594-1316
Fax: 301-402-0240
Email: masisond@helix.nih.gov

Education / Previous Training and Experience:
B.S., University of Massachusetts, Amherst, 1983
Ph.D., University of Massachusetts Medical Center, Worcester, 1993


Research Statement:

We are using genetics, molecular biology and biochemistry to identify and characterize cellular factors that influence propagation of the S. cerevisiae [PSI+] prion. [PSI+] is thought to be an amyloid form of Sup35, a protein involved in termination of protein synthesis. Amyloid is a highly structured fibrous aggregate. About two dozen human disorders, which include Type 2 diabetes and Alzheimer's disease, are associated with accumulation of amyloid forms of proteins. As an amyloid, [PSI+] propagates by recruiting the normal form of Sup35 and converting it into the same misshapen form as it joins the growing fiber. In addition to simply growing, transmissible [PSI+] particles, or prion "seeds", must replicate to be maintained in a growing yeast population. Our studies of mutations of the Hsp70 chaperone are revealing chaperone and co-chaperone interactions that are important for this seed replication activity.

Hsp70 is a universally conserved and essential protein chaperone that helps proteins adopt and maintain their native structural conformations. Hsp70 activity is regulated by co-chaperones, such as Hsp40. Hsp104 is another protein chaperone that acts with Hsp70 and Hsp40 to break up and reactivate proteins that have become aggregated. The normal function of this chaperone machine appears to promote amyloid propagation by breaking fibers into more numerous pieces, each of which can continue to propagate the amyloid structure. We have identified several mutations in these chaperones that variously affect the [PSI+] seeding process. Determining how these mutations affect their activities and their ability to interact with each other will help us understand the molecular mechanisms underlying the functions of this machinery. In addition to continuing the genetic characterization of the modified chaperones, current efforts focus on defining the physical interactions involved and on enzymatic analysis of the purified components.

We have also found that TPR co-chaperones, which are components of the Hsp90 machinery, can regulate Hsp70 function in [PSI+] propagation independently of Hsp90. We are using our system to dissect the mechanisms of how these co-chaperones regulate Hsp70 and Hsp90 function.

In addition to providing a better understanding of how protein chaperones function in amyloid propagation, our continued studies will provide insight into how they act in their many important roles in the cell.



Selected Publications:

Hung GC, Masison DC N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression. Genetics (173): 611-20, 2006. [Full Text/Abstract]

Yusuf Tutar, Youtao Song and Daniel C. Masison Primate Chaperones Hsc70 (Constitutive) and Hsp70 (Induced) Differ Functionally in Supporting Growth and Prion Propagation in Saccharomyces cerevisiae Genetics(172): 851-861, 2006. [Full Text/Abstract]

Wu YX, Greene LE, Masison DC, Eisenberg E Curing of yeast [PSI+] prion by guanidine inactivation of Hsp104 does not require cell division. Proc Natl Acad Sci U S A (102): 12789-94, 2005. [Full Text/Abstract]

Song Y, Masison DC Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). J Biol Chem (280): 34178-85, 2005. [Full Text/Abstract]

Song Y, Wu YX, Jung G, Tutar Y, Eisenberg E, Greene LE, Masison DC Role for Hsp70 Chaperone in Saccharomyces cerevisiae Prion Seed Replication. Eukaryot Cell (4): 289-97, 2005. [Full Text/Abstract]

Jones G Song Y Chung S Masison DC Propagation of Saccharomyces cerevisiae [PSI+] prion is impaired by factors that regulate Hsp70 substrate binding. Mol. Cell. Biol.(24): 3928-3937, 2004. [Full Text/Abstract]

Jones GW Song Y Masison DC Deletion of the Hsp70 chaperone gene SSB causes hypersensitivity to guanidine toxicity and curing of the [PSI+] prion by increasing guanidine uptake in yeast. Mol Genet Genomics (269): 304-11, 2003. [Full Text/Abstract]

Jones GW Masison DC Saccharomyces cerevisiae Hsp70 mutations affect [PSI+] prion propagation and cell growth differently and implicate Hsp40 and tetratricopeptide repeat cochaperones in impairment of [PSI+]. Genetics (163): 495-506, 2003. [Full Text/Abstract]

Jung G Jones G Masison DC Amino acid residue 184 of yeast Hsp104 chaperone is critical for prion-curing by guanidine, prion propagation, and thermotolerance. Proc Natl Acad Sci U S A (99): 9936-41, 2002. [Full Text/Abstract]

Schwimmer C Masison DC Antagonistic interactions between yeast [PSI(+)] and [URE3] prions and curing of [URE3] by Hsp70 protein chaperone Ssa1p but not by Ssa2p. Mol Cell Biol (22): 3590-8, 2002. [Full Text/Abstract]

Jung G Masison DC Guanidine hydrochloride inhibits Hsp104 activity in vivo: a possible explanation for its effect in curing yeast prions. Curr Microbiol (43): 7-10, 2001. [Full Text/Abstract]

Jung G Jones G Wegrzyn RD Masison DC A role for cytosolic hsp70 in yeast [PSI(+)] prion propagation and [PSI(+)] as a cellular stress. Genetics (156): 559-70, 2000. [Full Text/Abstract]



Page last updated: December 17, 2008

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