Systems and Approaches
microscopy, molecular imaging, high-throughput microscopy, Image Express, FACS, yeast, biochemistry, deconvolution microscopy, genetics, genomics, Zeiss LSM 710, high throughput yeast genome screens

Interests
quality control of protein folding, protein aggregation, molecular basis for aggregation-induced toxicity, prions, neurodegenerative diease, stem cells, quality control of protein folding in stem cells, how stem cells deal with protein damage

Summary
I am interested in the way cells deal with protein damage. Within the cell, proper protein folding is maintained by the protein folding quality control machinery, which includes a network of cellular chaperones, tasked with helping proteins reach and maintain their native fold. Avoiding protein damage is essential to maintaining the protein folding homeostasis of the cell. Disrupting this "proteostasis" can lead to cell death and to the inactivation of poorly folded "meta-stable" proteins, that require chaperone assistance for function, leading to cellular deregulation and cancer. One of my interests is the regulated accumulation of misfolded and aggregated proteins in intracellular inclusions, which are a hallmark of many neurodegenerative diseases, including Parkinson's, Huntington’s and Prion Disease. Recently, we identified two distinct intracellular compartments for the sequestration of misfolded cytosolic proteins. Partition of quality control substrates to either compartment appears to depend on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins awaiting degradation by the proteasome accumulate in a juxtanuclear compartment. In contrast, terminally aggregated proteins are sequestered in a perivacuolar inclusion linked to the autophagic pathway. Strikingly, disease-associated Huntingtin and prion proteins are preferentially directed to the perivacuolar compartment. Enhancing ubiquitination of a prion protein suffices to promote its delivery to the juxtanuclear inclusion. The identification of ubiquitination as a signal directing misfolded proteins to distinct subcellular quality control compartments provides a framework for understanding the preferential accumulation of amyloidogenic proteins linked to human disease. Since all proteins can aggregate is it striking that only a few do in fact accumulate in aggregate inclusions associate in neurodegenerative diseases. Hence, one of my goals is to understand the molecular basis of the toxicity induced by the aggregation of disease-associated proteins. I am also studying how human embryonic stem cells avoid the accumulation of protein damage. These cells are around long enough to accumulate protein folding damage from stress and mutations, yet it is critical that stem cells avoid the perpetuation of damage to other differentiated cells in the body, and the germ line which is passed on to the succeeding generation.

Published by Dan Kaganovich

Protein Quality Control: On IPODs and Other JUNQ.

Bagola K and Sommer T

Current biology : CB 18(21):R1019-21, 2008 Nov 11 - Who cited this? | PubMed ID: 19000801 | Fulltext

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Misfolded proteins partition between two distinct quality control compartments.

Kaganovich D, Kopito R, and Frydman J

Nature 454(7208):1088, 2008 Aug 28 - Who cited this? | PubMed ID: 18756251 | Fulltext

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Protein quality control: chaperones culling corrupt conformations.

McClellan AJ, Tam S, Kaganovich D, and Frydman J

Nature cell biology 7(8):736, 2005 Aug - Who cited this? | PubMed ID: 16056264 | Fulltext

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Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes. Evidence for peptide-induced channel opening in the alpha-rings.

Kisselev AF, Kaganovich D, and Goldberg AL

The Journal of biological chemistry 277(25):22260, 2002 Jun 21 - Who cited this? | PubMed ID: 11927581 | Fulltext

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Cleavage of cyclin A at R70/R71 by the bacterial protease OmpT.

Yam CH, Siu WY, Kaganovich D, Ruderman JV, and Poon RY

Proceedings of the National Academy of Sciences of the United States of America 98(2):497, 2001 Jan 16 - Who cited this? | PubMed ID: 11136238 | Fulltext

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Education

School:
Stanford University 2002-2007
PhD Molecular and Cellular Biology
School:
Harvard University 1997-2001
AB Cum Laude Biochemistry