Bio
Research & Scholarship
Current Research and Scholarly Interests
The Brandman Lab studies how cells ensure protein quality and how they signal stress. To achieve this, we employ an integrated set of techniques including single cell anaysis of stress pathways, structural studies, in vitro translation, and full genome screens in yeast and mammalian cells.
Teaching
2017-18 Courses
- Advanced Cell Biology
BIO 214, BIOC 224, MCP 221 (Win) - Biochemistry Bootcamp
BIOC 202 (Aut) - Developing an Original Research Proposal
BIOC 360 (Win) -
Independent Studies (8)
- Directed Reading in Biochemistry
BIOC 299 (Aut, Win, Spr, Sum) - Directed Reading in Biophysics
BIOPHYS 399 (Win, Spr, Sum) - Graduate Research
BIOPHYS 300 (Win, Spr) - Graduate Research and Special Advanced Work
BIOC 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
BIOC 370 (Aut, Win, Spr, Sum) - Out-of-Department Graduate Research
BIO 300X (Aut, Win, Spr, Sum) - The Teaching of Biochemistry
BIOC 221 (Aut, Win, Spr, Sum) - Undergraduate Research
BIOC 199 (Aut, Win, Spr, Sum)
- Directed Reading in Biochemistry
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Prior Year Courses
2016-17 Courses
- Biochemistry Bootcamp
BIOC 202 (Aut) - Developing an Original Research Proposal
BIOC 360 (Win, Spr)
2015-16 Courses
- Biochemistry Bootcamp
BIOC 202 (Aut) - Developing an Original Research Proposal
BIOC 360 (Win, Spr)
2014-15 Courses
- Biochemistry Bootcamp
BIOC 202 (Aut) - Developing an Original Research Proposal
BIOC 360 (Aut, Win, Spr)
- Biochemistry Bootcamp
Stanford Advisees
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Doctoral Dissertation Reader (AC)
. Ei Cho, Alexander Johnson -
Postdoctoral Faculty Sponsor
Zoe Davis, Zane Jaafar
Publications
All Publications
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Ribosome-associated protein quality control.
Nature structural & molecular biology
2016; 23 (1): 7–15
Abstract
Protein synthesis by the ribosome can fail for numerous reasons including faulty mRNA, insufficient availability of charged tRNAs and genetic errors. All organisms have evolved mechanisms to recognize stalled ribosomes and initiate pathways for recycling, quality control and stress signaling. Here we review the discovery and molecular dissection of the eukaryotic ribosome-associated quality-control pathway for degradation of nascent polypeptides arising from interrupted translation.
View details for DOI 10.1038/nsmb.3147
View details for PubMedID 26733220
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Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains.
Science
2015; 347 (6217): 75-78
Abstract
In Eukarya, stalled translation induces 40S dissociation and recruitment of the ribosome quality control complex (RQC) to the 60S subunit, which mediates nascent chain degradation. Here we report cryo-electron microscopy structures revealing that the RQC components Rqc2p (YPL009C/Tae2) and Ltn1p (YMR247C/Rkr1) bind to the 60S subunit at sites exposed after 40S dissociation, placing the Ltn1p RING (Really Interesting New Gene) domain near the exit channel and Rqc2p over the P-site transfer RNA (tRNA). We further demonstrate that Rqc2p recruits alanine- and threonine-charged tRNA to the A site and directs the elongation of nascent chains independently of mRNA or 40S subunits. Our work uncovers an unexpected mechanism of protein synthesis, in which a protein--not an mRNA--determines tRNA recruitment and the tagging of nascent chains with carboxy-terminal Ala and Thr extensions ("CAT tails").
View details for DOI 10.1126/science.1259724
View details for PubMedID 25554787
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A Ribosome-Bound Quality Control Complex Triggers Degradation of Nascent Peptides and Signals Translation Stress
CELL
2012; 151 (5): 1042-1054
Abstract
The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism.
View details for DOI 10.1016/j.cell.2012.10.044
View details for Web of Science ID 000311423500017
View details for PubMedID 23178123
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Feedback loops shape cellular signals in space and time
SCIENCE
2008; 322 (5900): 390-395
Abstract
Positive and negative feedback loops are common regulatory elements in biological signaling systems. We discuss core feedback motifs that have distinct roles in shaping signaling responses in space and time. We also discuss approaches to experimentally investigate feedback loops in signaling systems.
View details for DOI 10.1126/science.1160617
View details for Web of Science ID 000260094500033
View details for PubMedID 18927383
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STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels
CELL
2007; 131 (7): 1327-1339
Abstract
Deviations in basal Ca2+ levels interfere with receptor-mediated Ca2+ signaling as well as endoplasmic reticulum (ER) and mitochondrial function. While defective basal Ca2+ regulation has been linked to various diseases, the regulatory mechanism that controls basal Ca2+ is poorly understood. Here we performed an siRNA screen of the human signaling proteome to identify regulators of basal Ca2+ concentration and found STIM2 as the strongest positive regulator. In contrast to STIM1, a recently discovered signal transducer that triggers Ca2+ influx in response to receptor-mediated depletion of ER Ca2+ stores, STIM2 activated Ca2+ influx upon smaller decreases in ER Ca2+. STIM2, like STIM1, caused Ca2+ influx via activation of the plasma membrane Ca2+ channel Orai1. Our study places STIM2 at the center of a feedback module that keeps basal cytosolic and ER Ca2+ concentrations within tight limits.
View details for DOI 10.1016/j.cell.2007.11.039
View details for Web of Science ID 000252217200021
View details for PubMedID 18160041
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Interlinked fast and slow positive feedback loops drive reliable cell decisions
SCIENCE
2005; 310 (5747): 496-498
Abstract
Positive feedback is a ubiquitous signal transduction motif that allows systems to convert graded inputs into decisive, all-or-none outputs. Here we investigate why the positive feedback switches that regulate polarization of budding yeast, calcium signaling, Xenopus oocyte maturation, and various other processes use multiple interlinked loops rather than single positive feedback loops. Mathematical simulations revealed that linking fast and slow positive feedback loops creates a "dual-time" switch that is both rapidly inducible and resistant to noise in the upstream signaling system.
View details for DOI 10.1126/science.1113834
View details for Web of Science ID 000232786000048
View details for PubMedID 16239477
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Protein evolution in the context of Drosophila development
JOURNAL OF MOLECULAR EVOLUTION
2005; 60 (6): 774-U42
Abstract
The tempo at which a protein evolves depends not only on the rate at which mutations arise but also on the selective effects that those mutations have at the organismal level. It is intuitive that proteins functioning during different stages of development may be predisposed to having mutations of different selective effects. For example, it has been hypothesized that changes to proteins expressed during early development should have larger phenotypic consequences because later stages depend on them. Conversely, changes to proteins expressed much later in development should have smaller consequences at the organismal level. Here we assess whether proteins expressed at different times during Drosophila development vary systematically in their rates of evolution. We find that proteins expressed early in development and particularly during mid-late embryonic development evolve unusually slowly. In addition, proteins expressed in adult males show an elevated evolutionary rate. These two trends are independent of each other and cannot be explained by peculiar rates of mutation or levels of codon bias. Moreover, the observed patterns appear to hold across several functional classes of genes, although the exact developmental time of the slowest protein evolution differs among each class. We discuss our results in connection with data on the evolution of development.
View details for DOI 10.1007/s00239-004-0241-2
View details for Web of Science ID 000230077700008
View details for PubMedID 15909223