Boards, Advisory Committees, Professional Organizations
Member, Stanford Synchrotron Radiation Lightsource Users' Organization Executive Committee (2013 - Present)
Bachelor of Science, University of California San Diego (2006)
Doctor of Philosophy, California Institute of Technology (2013)
Judith Frydman, Postdoctoral Faculty Sponsor
Cotranslational signal-independent SRP preloading during membrane targeting
2016; 536 (7615): 224-?
Ribosome-associated factors must properly decode the limited information available in nascent polypeptides to direct them to their correct cellular fate. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum, involving recognition of linear hydrophobic signal sequences or transmembrane domains by the signal recognition particle (SRP). Notably, the SRP has low abundance relative to the large number of ribosome-nascent-chain complexes (RNCs), yet it accurately selects those destined for the endoplasmic reticulum. Despite their overlapping specificities, the SRP and the cotranslationally acting Hsp70 display precise mutually exclusive selectivity in vivo for their cognate RNCs. To understand cotranslational nascent chain recognition in vivo, here we investigate the cotranslational membrane-targeting cycle using ribosome profiling in yeast cells coupled with biochemical fractionation of ribosome populations. We show that the SRP preferentially binds secretory RNCs before their targeting signals are translated. Non-coding mRNA elements can promote this signal-independent pre-recruitment of SRP. Our study defines the complex kinetic interaction between elongation in the cytosol and determinants in the polypeptide and mRNA that modulate SRP–substrate selection and membrane targeting.
View details for DOI 10.1038/nature19309
View details for Web of Science ID 000381472100039
View details for PubMedID 27487213
Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on alpha-Synuclein
2015; 85 (1): 76-87
Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and α-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.
View details for DOI 10.1016/j.neuron.2014.11.027
View details for Web of Science ID 000348295100010
Local slowdown of translation by nonoptimal codons promotes nascent-chain recognition by SRP in vivo.
Nature structural & molecular biology
2014; 21 (12): 1100-1105
The genetic code allows most amino acids a choice of optimal and nonoptimal codons. We report that synonymous codon choice is tuned to promote interaction of nascent polypeptides with the signal recognition particle (SRP), which assists in protein translocation across membranes. Cotranslational recognition by the SRP in vivo is enhanced when mRNAs contain nonoptimal codon clusters 35-40 codons downstream of the SRP-binding site, the distance that spans the ribosomal polypeptide exit tunnel. A local translation slowdown upon ribosomal exit of SRP-binding elements in mRNAs containing these nonoptimal codon clusters is supported experimentally by ribosome profiling analyses in yeast. Modulation of local elongation rates through codon choice appears to kinetically enhance recognition by ribosome-associated factors. We propose that cotranslational regulation of nascent-chain fate may be a general constraint shaping codon usage in the genome.
View details for DOI 10.1038/nsmb.2919
View details for PubMedID 25420103
- Local slowdown of translation by nonoptimal codons promotes nascent-chain recognition by SRP in vivo NATURE STRUCTURAL & MOLECULAR BIOLOGY 2014; 21 (12): 1100-1105