Raymond J. Deshaies
California Institute of Technology
Cyclin-dependent kinaseF-box proteinUbiquitin ligaseMutantEndoplasmic reticulumCell division control protein 4Ubiquitin-conjugating enzymeChemistryUbiquitinProteasomeCUL1Saccharomyces cerevisiaeCullinSic1COP9 signalosomeNEDD8Cell cycleProtein degradationBiochemistryBiologyCell biology
Publications 208
#1Jennifer L. Mamrosh (California Institute of Technology)H-Index: 3
#2Jixi Li (California Institute of Technology)H-Index: 21
Last. Raymond J. Deshaies (California Institute of Technology)H-Index: 94
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Protein degradation products are constitutively presented as peptide antigens by MHC Class I. While hypervariability of Class I genes is known to tremendously impact antigen presentation, whether differential function of protein degradation pathways (comprising >1000 genes) could alter antigen generation remains poorly understood apart from a few model substrates. In this study, we introduce normalization methods for quantitative antigen mass spectrometry and confirm that most Class I antigens a...
#1Tanya R. Porras-Yakushi (California Institute of Technology)H-Index: 6
#2Justin M. Reitsma (California Institute of Technology)H-Index: 15
Last. Sonja Hess (California Institute of Technology)H-Index: 45
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Proteasome inhibitors are an important class of chemotherapeutic drugs. In this study, we performed a large-scale ubiquitylome analysis of the three proteasome inhibitors MG132, bortezomib and carfilzomib. Although carfilzomib is currently being used for the treatment of multiple myeloma, it has not yet been subjected to a global ubiquitylome analysis. In this study, we identified more than 14,000 unique sites of ubiquitylation in more than 4400 protein groups. We introduced stringent criteria t...
#1Gang Zhang (California Institute of Technology)H-Index: 1
#2Shan Li (California Institute of Technology)H-Index: 6
Last. Tsui-Fen Chou (California Institute of Technology)H-Index: 22
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Abstract Small-molecule inhibitors of p97 are useful tools to study p97 function. Human p97 is an important AAA ATPase due to its diverse cellular functions and implication in mediating the turnover of proteins involved in tumorigenesis and virus infections. Multiple p97 inhibitors identified from previous high-throughput screening studies are thiol-reactive compounds targeting Cys522 in the D2 ATP-binding domain. Thus, these findings suggest a potential strategy to develop covalent p97 inhibito...
3 CitationsSource
#1Blanca Arango-Gonzalez (University of Tübingen)H-Index: 18
#2Merve Sen (University of Tübingen)H-Index: 2
Last. Marius Ueffing (University of Tübingen)H-Index: 72
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Due to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here...
4 CitationsSource
#1Seung-Joo Yang (Gwangju Institute of Science and Technology)H-Index: 4
#2Seung-Je Jeon (Gwangju Institute of Science and Technology)H-Index: 1
Last. Kwang Min Lee (PNU: Pusan National University)H-Index: 8
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Cereblon (CRBN), a substrate receptor for Cullin-ring E3 ubiquitin ligase (CRL), is a major target protein of immunomodulatory drugs. An earlier study demonstrated that CRBN directly interacts with the catalytic alpha subunit of AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, down-regulating the enzymatic activity of AMPK. However, it is not clear how CRBN modulates AMPK activity. To investigate the mechanism of CRBN-dependent AMPK inhibition, we measured protein l...
10 CitationsSource
The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin—a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of ‘rational drug discovery’ methodology in the 1970s, followed by the ...
58 CitationsSource
#1Kurt M. Reichermeier (California Institute of Technology)H-Index: 5
#2Ronny Straube (MPG: Max Planck Society)H-Index: 1
Last. Donald S. Kirkpatrick (Genentech)H-Index: 51
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Summary Co-opting Cullin4 RING ubiquitin ligases (CRL4s) to inducibly degrade pathogenic proteins is emerging as a promising therapeutic strategy. Despite intense efforts to rationally design degrader molecules that co-opt CRL4s, much about the organization and regulation of these ligases remains elusive. Here, we establish protein interaction kinetics and estimation of stoichiometries (PIKES) analysis, a systematic proteomic profiling platform that integrates cellular engineering, affinity puri...
16 CitationsSource
#1Rati Verma (Amgen)H-Index: 1
#2Dane Mohl (Amgen)H-Index: 1
Last. Raymond J. Deshaies (Amgen)H-Index: 94
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Two decades into the twenty-first century, a confluence of breakthrough technologies wielded at the molecular level is presenting biologists with unique opportunities to unravel the complexities of the cellular world. CRISPR/Cas9 allows gene knock-outs, knock-ins, and single-base editing at chromosomal loci. RNA-based tools such as siRNA, antisense oligos, and morpholinos can be used to silence expression of specific genes. Meanwhile, protein knockdown tools that draw inspiration from natural re...
71 CitationsSource
A process termed ubiquitination mediates the regulated destruction of cellular proteins, thereby preventing disease or infection. Structural data now reveal how a crucial regulator of ubiquitination enzymes coordinates this process. Structural data reveal a key step that regulates protein degradation.
1 CitationsSource
#1Kankan Wang (Purdue University)H-Index: 1
#2Raymond J. Deshaies (Amgen)H-Index: 94
Last. Xing Liu (Purdue University)H-Index: 15
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Cullin-RING ubiquitin ligases (CRLs) determine the substrate specificity of ubiquitination reactions, and substrates are recruited to the cullin core through binding to their cognate substrate receptor modules. Because a family of substrate receptors compete for the same cullin core, the assembly and activity of CRLs are dynamically regulated to fulfill the needs of the cell to adapt to the changing pool of proteins demanding ubiquitination. Cullins are modified by NEDD8, a ubiquitin-like protei...
10 CitationsSource