Ruprecht-Karls-Universität Heidelberg
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Joazeiro0117 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Joazeiro, Claudio
Application deadline:
31. Jul 2017
Start of PhD project:
1. Sep 2017

Project description:

Ribosome-associated quality control and neurodegeneration
Broadly, we are interested in understanding how cells know when its proteins are aberrant or damaged to then decide on ways to either correct or eliminate them, and in how defects in such protein quality control processes lead to neurodegeneration.
Our earlier work had shown that mutation of the E3 ligase, Listerin, causes neurodegeneration in mice (1); in many respects, Listerin-mutant mice resemble commonly utilized mouse models of Amyotrophic Lateral Sclerosis (ALS). Subsequently, we elucidated the function of the yeast Listerin ortholog (Ltn1) by showing that it acts in a novel protein quality control pathway taking place on ribosomes, now known as Ribosome-Associated Quality Control (RQC). Specifically, Ltn1 binds to ribosomes that become stalled during translational elongation and targets the associated nascent polypeptide chains for ubiquitylation and degradation (2). Since defective protein quality control is a hallmark of neurodegeneration, these findings suggest that the yeast model may be predictive of molecular mechanisms underlying neurodegeneration in the Listerin-mutant mice.

Ltn1 functions as a component of the ribosome-associated quality control (RQC) complex, along with Rqc1 and Rqc2 (NEMF in mammals) subunits (3,4). We solved the first cryo-EM structure of this complex, revealing that Rqc2 is responsible for recognizing the stalled 60S ribosomal subunit and recruiting Ltn1, which, in turn, is properly positioned to directly ubiquitylate the aberrant nascent chain (5-7).

Depending on the applicant’s background and interests, the available projects are (1) to study fundamental aspects of RQC function and mechanism, and (2) to utilize the available knowledge acquired from yeast and other models to elucidate molecular mechanisms of neurodegeneration in RQC-mutant mice.
(1) Chu, J. et al. A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration. Proc Natl Acad Sci U S A 106, 2097-2103 (2009)

(2) Bengtson, M. H. & Joazeiro, C. A. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature 467, 470-473 (2010).

(3) Brandman, O. et al. A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress. Cell 151, 1042-1054 (2012)

(4) Defenouillere, Q. et al. Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products. Proc. Natl. Acad. Sci. USA 110, 5046-5051 (2013)

(5) Lyumkis, D. et al. Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex. Proc Natl Acad Sci U S A 111, 15981-15986 (2014)

(6) Shao, S., Brown, A., Santhanam, B. & Hegde, R. S. Structure and assembly pathway of the ribosome quality control complex. Mol Cell 57, 433-444 (2015)

(7) Shen, P. S. et al. Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347, 75-78 (2015)

(8) Yonashiro, R. et al. The Rqc2/Tae2 subunit of the Ribosome-Associated Quality Control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife 5, e11794 (2016)
Methods that will be used:
Methods utilized will be among, but not limited, to the following:

• Genetic manipulation of the yeast, S. cerevisiae, including genetic screens
• Genetic manipulation of mice
• Biochemical analyses of yeast strains (immunoblot, immunoprecipitation, sucrose gradient fractionation, etc.)
• Biochemical and immunohistochemical analyses of mouse tissues
• Fluorescence imaging techniques to analyse protein expression and subcellular distribution
• Characterization of motor defects of mutant mice
Cooperation partners:
Personal qualifications:
• B.S. and/or M.S. in Biochemistry, Molecular Biology, Neurobiology, or related disciplines
• Excellent previous Academic performance
• Strong analytical and technical skills
• Good English language skills (no German language requirement)
• Problem-solving, proactive attitude
Listerin/Ltn1 E3 ligase, RQC, Protein quality control, Neurodegeneration, ALS