J. W. Harper
Baylor College of Medicine
Ubiquitin ligaseMolecular biologyUbiquitinBiologyCell biology
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Publications 280
#1Raquel C. Martinez-Chacin (UNC: University of North Carolina at Chapel Hill)H-Index: 1
#2Tatyana Bodrug (UNC: University of North Carolina at Chapel Hill)
Last. Gavin D. Grant (UNC: University of North Carolina at Chapel Hill)H-Index: 4
view all 15 authors...
The interplay between E2 and E3 enzymes regulates the polyubiquitination of substrates in eukaryotes. Among the several RING-domain E3 ligases in humans, many utilize two distinct E2s for polyubiquitination. For example, the cell cycle regulatory E3, human anaphase-promoting complex/cyclosome (APC/C), relies on UBE2C to prime substrates with ubiquitin (Ub) and on UBE2S to extend polyubiquitin chains. However, the potential coordination between these steps in ubiquitin chain formation remains und...
#1Constance S. Petit (Harvard University)H-Index: 3
#2Jane J. Lee (Harvard University)
Last. Sara Haque (Harvard University)
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Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing P...
#1Paul J. Wrighton (Brigham and Women's Hospital)H-Index: 5
#2Arkadi Shwartz (Brigham and Women's Hospital)H-Index: 4
Last. Wolfram Goessling (Brigham and Women's Hospital)H-Index: 34
view all 7 authors...
Mitophagy defects are linked to aging, sarcopenia, and neurodegenerative diseases. To target this process for clinical intervention, the in vivo mitophagy dynamics and molecular mechanisms under physiologically relevant stresses must be better understood. Here, we characterized newly generated mitophagy reporter zebrafish and discovered high basal mitophagy rates in many organs during embryonic development and organogenesis. Rapid time-lapse imaging revealed in vivo dynamics of fasting-induced m...
#1Alban Ordureau (Harvard University)H-Index: 20
#2Joao A. Paulo (Harvard University)H-Index: 27
Last. J. W. Harper (Harvard University)H-Index: 101
view all 9 authors...
Summary The ubiquitin ligase Parkin, protein kinase PINK1, USP30 deubiquitylase, and p97 segregase function together to regulate turnover of damaged mitochondria via mitophagy, but our mechanistic understanding in neurons is limited. Here, we combine induced neurons (iNeurons) derived from embryonic stem cells with quantitative proteomics to reveal the dynamics and specificity of Parkin-dependent ubiquitylation under endogenous expression conditions. Targets showing elevated ubiquitylation in US...
3 CitationsSource
#1Edward L. Huttlin (Harvard University)H-Index: 28
#2Raphael J. Bruckner (Harvard University)H-Index: 6
Last. Steven P. Gygi (Harvard University)H-Index: 143
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Thousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome. Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins - half the proteome - in 293T cells and includes 118,162 interactions among 14,586 proteins; the second results from 5,522 immunoprecipitations in HCT116 cells...
1 CitationsSource
#1Heeseon An (Harvard University)H-Index: 9
#2J. W. Harper (Harvard University)H-Index: 101
Abstract Ribosomes are central to the life of a cell, as they translate the genetic code into the amino acid language of proteins. Moreover, ribosomal abundance within the cell is coordinated with protein production required for cell function or processes such as cell division. As such, it is not surprising that these elegant machines are both highly regulated at the level of both their output of newly translated proteins but also at the level of ribosomal protein expression, ribosome assembly, ...
#1Tim Ahfeldt (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 11
#1Tim Ahfeldt (ISMMS: Icahn School of Medicine at Mount Sinai)
Last. L RubinLee (Harvard University)H-Index: 53
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Summary Parkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. W...
#1Naiara Santana-Codina (Harvard University)H-Index: 5
#2Sebastian Gableske (Harvard University)H-Index: 3
Last. Joseph D. Mancias (Harvard University)H-Index: 19
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We thank Nai and colleagues for their interest in our recently published paper, Santana-Codina et al .,[1][1] and their comment, also published in Haematologica.[2][2] Their comment, containing new unpublished experimental data, questions the importance of nuclear receptor co-activator 4 (NCOA4) in
#1Colin D. Gottlieb (Stanford University)H-Index: 2
#2Airlia C. S. Thompson (Stanford University)H-Index: 1
Last. Ron R. Kopito (Stanford University)H-Index: 61
view all 5 authors...
2 CitationsSource
#1Jin-Mi Heo (Harvard University)H-Index: 5
#2Nathan J. Harper (Harvard University)H-Index: 1
Last. J. W. Harper (Harvard University)H-Index: 101
view all 8 authors...
The PINK1 protein kinase activates the PARK2 ubiquitin ligase to promote mitochondrial ubiquitylation and recruitment of ubiquitin-binding mitophagy receptors typified by OPTN and TAX1BP1. Here, we combine proximity biotinylation of OPTN and TAX1BP1 with CRISPR-Cas9–based screens for mitophagic flux to develop a spatial proteogenetic map of PARK2-dependent mitophagy. Proximity labeling of OPTN allowed visualization of a “mitochondrial-autophagosome synapse” upon mitochondrial depolarization. Pro...
1 CitationsSource