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A Study of Protein Targeting Reveals Insights into Mitigating Protein Aggregation


Nguyen, Thang Xuan (2013) A Study of Protein Targeting Reveals Insights into Mitigating Protein Aggregation. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JA4R-TE24.


A unique chloroplast Signal Recognition Particle (SRP) in green plants is primarily dedicated to the post-translational targeting of light harvesting chlorophyll-a/b binding (LHC) proteins. Our study of the thermodynamics and kinetics of the GTPases of the system demonstrates that GTPase complex assembly and activation are highly coupled in the chloroplast GTPases, suggesting they may forego the GTPase activation step as a key regulatory point. This reflects adaptations of the chloroplast SRP to the delivery of their unique substrate protein. Devotion to one highly hydrophobic family of proteins also may have allowed the chloroplast SRP system to evolve an efficient chaperone in the cpSRP43 subunit. To understand the mechanism of disaggregation, we showed that LHC proteins form micellar, disc-shaped aggregates that present a recognition motif (L18) on the aggregate surface. Further molecular genetic and structure-activity analyses reveal that the action of cpSRP43 can be dissected into two steps: (i) initial recognition of L18 on the aggregate surface; and (ii) aggregate remodeling, during which highly adaptable binding interactions of cpSRP43 with hydrophobic transmembrane domains of the substrate protein compete with the packing interactions within the aggregate. We also tested the adaptability of cpSRP43 for alternative substrates, specifically in attempts to improve membrane protein expression and inhibition of amyloid beta fibrillization. These preliminary results attest to cpSRP43’s potential as a molecular chaperone and provides the impetus for further engineering endeavors to address problems that stem from protein aggregation.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Chaperone; Disaggregase; Signal Recognition Particle; membrane protein; kinetics
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Shan, Shu-ou
Thesis Committee:
  • Clemons, William M. (chair)
  • Hsieh-Wilson, Linda C.
  • Chan, David C.
  • Shan, Shu-ou
Defense Date:31 May 2013
Non-Caltech Author Email:ngxthang (AT)
Record Number:CaltechTHESIS:06052013-151748060
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7845
Deposited By: Thang Nguyen
Deposited On:06 Jun 2013 22:41
Last Modified:04 Oct 2019 00:01

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