Advisory Committee Chair
Bingdong Sha
Advisory Committee Members
Champion Cs Deivanayagam
Fangtsyr Lin
Weeichin Lin
Peter Edward Prevelige
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Molecular chaperones are a large group of proteins that bind and stabilize nascent polypeptides and facilitate protein folding. One major function of chaperones is to bind hydrophobic segments of nascent polypeptides to prevent them from aggregating. How chaperone Hsp40 recognizes and interacts with polypeptides and cooperates with chaperone Hsp70 is a fundamental question. The crystal structure of the putative peptide-binding fragment of Hdj1, a human member of the type II Hsp40 family was determined, suggesting the domain I of Hsp40 may possess significant flexibility which is important for Hsp40 to regulate the size of the cleft. The flexibility may be utilized to facilitate the interaction between polypeptides and Hsp40, and the transfer of polypeptides to Hsp70. TA proteins are membrane proteins with a distinct C-terminal transmembrane domain (TMD). TA protein integration into the ER membrane requires the cooperation of chaperone. Yeast Golgi ER trafficking (GET) complex including Get1, Get2, and Get3 is identified to facilitate TA protein post-translational integration into the ER membrane. Get3 is a soluble cytosolic ATPase, which recognizes and binds TMD of TA proteins. The crystal structures of S. cerevisiae and D. hanenii Get3 were determined. The crystal structures reveal that Get3 forms a homo-dimer driven by an unusual inter-molecular Zinc-finger motif. Each monomer of Get3 contains a nucleotide-binding domain (NBD) and a finger domain. The finger domain contains a hydrophobic groove which is a putative TMD binding site. Get3 adopts a nucleotide-free "open" conformation or a nucleotide-bound "closed" conformation. NBD of two monomers are swung sway from each other in "open" conformation, and make close contact with each other in "closed" conformation. By switching between two conformations Get3 may facilitate TA protein integration into the ER membrane.
Recommended Citation
Hu, Junbin, "Structural and functional studies on heat shock protein Hsp40-Hdj1 and Golgi ER trafficking protein Get3" (2009). All ETDs from UAB. 1981.
https://digitalcommons.library.uab.edu/etd-collection/1981
