
@article {891,
	title = {Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies.},
	journal = {J Biol Chem},
	volume = {290},
	year = {2015},
	month = {2015 Mar 13},
	pages = {7003-15},
	abstract = {<p>The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding α-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca(2+) sensitivity of human β-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca(2+) activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca(2+) concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis.</p>
},
	keywords = {Actins, Adenosine Triphosphatases, Calcium, Cardiomyopathies, Humans, Models, Molecular, Myosins, Point Mutation, Protein Stability, Tropomyosin},
	issn = {1083-351X},
	doi = {10.1074/jbc.M114.596676},
	author = {Gupte, Tejas M and Haque, Farah and Gangadharan, Binnu and Sunitha, Margaret S and Mukherjee, Souhrid and Anandhan, Swetha and Rani, Deepa Selvi and Mukundan, Namita and Jambekar, Amruta and Thangaraj, Kumarasamy and Sowdhamini, Ramanathan and Sommese, Ruth F and Nag, Suman and Spudich, James A and Mercer, John A}
}
@article {1012,
	title = {Mitochondrial Fragmentation Due to Inhibition of Fusion Increases Cyclin B through Mitochondrial Superoxide Radicals.},
	journal = {PLoS One},
	volume = {10},
	year = {2015},
	month = {2015},
	pages = {e0126829},
	abstract = {<p>During the cell cycle, mitochondria undergo regulated changes in morphology. Two particularly interesting events are first, mitochondrial hyperfusion during the G(1)-S transition and second, fragmentation during entry into mitosis. The mitochondria remain fragmented between late G(2)- and mitotic exit. This mitotic mitochondrial fragmentation constitutes a checkpoint in some cell types, of which little is known. We bypass the {\textquoteright}mitotic mitochondrial fragmentation{\textquoteright} checkpoint by inducing fragmented mitochondrial morphology and then measure the effect on cell cycle progression. Using Drosophila larval hemocytes, Drosophila S2R(+) cell and cells in the pouch region of wing imaginal disc of Drosophila larvae we show that inhibiting mitochondrial fusion, thereby increasing fragmentation, causes cellular hyperproliferation and an increase in mitotic index. However, mitochondrial fragmentation due to over-expression of the mitochondrial fission machinery does not cause these changes. Our experiments suggest that the inhibition of mitochondrial fusion increases superoxide radical content and leads to the upregulation of cyclin B that culminates in the observed changes in the cell cycle. We provide evidence for the importance of mitochondrial superoxide in this process. Our results provide an insight into the need for mitofusin-degradation during mitosis and also help in understanding the mechanism by which mitofusins may function as tumor suppressors.</p>
},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0126829},
	author = {Gupte, Tejas M}
}
