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Full-Text Articles in Medicine and Health Sciences

Autophosphorylation Of The Smk1 Mapk Is Spatially And Temporally Regulated By Ssp2 During Meiotic Development In Yeast., Chong Wai Tio, Gregory Omerza, Sham Sunder, Edward Winter Oct 2015

Autophosphorylation Of The Smk1 Mapk Is Spatially And Temporally Regulated By Ssp2 During Meiotic Development In Yeast., Chong Wai Tio, Gregory Omerza, Sham Sunder, Edward Winter

Department of Biochemistry and Molecular Biology Faculty Papers

Smk1 is a meiosis-specific MAPK that controls spore wall morphogenesis in Saccharomyces cerevisiae. Although Smk1 is activated by phosphorylation of the threonine (T) and tyrosine (Y) in its activation loop, it is not phosphorylated by a dual-specificity MAPK kinase. Instead, the T is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase, Cak1. The Y is autophosphorylated in an intramolecular reaction that requires a meiosis-specific protein named Ssp2. The meiosis-specific CDK-like kinase, Ime2, was previously shown to positively regulate Smk1. Here we show that Ime2 activity is required to induce the translation of SSP2 mRNA at anaphase II. Ssp2 protein is then …


Atomic Structure Of Grk5 Reveals Distinct Structural Features Novel For G Protein-Coupled Receptor Kinases, Konstantin E. Komolov, Anshul Bhardwaj, Jeffrey L. Benovic Aug 2015

Atomic Structure Of Grk5 Reveals Distinct Structural Features Novel For G Protein-Coupled Receptor Kinases, Konstantin E. Komolov, Anshul Bhardwaj, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5'-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly …


The Rise And Fall Of Poly(Adp-Ribose): An Enzymatic Perspective., John M. Pascal, Tom Ellenberger Aug 2015

The Rise And Fall Of Poly(Adp-Ribose): An Enzymatic Perspective., John M. Pascal, Tom Ellenberger

Department of Biochemistry and Molecular Biology Faculty Papers

Human cells respond to DNA damage with an acute and transient burst in production of poly(ADP-ribose), a posttranslational modification that expedites damage repair and plays a pivotal role in cell fate decisions. Poly(ADP-ribose) polymerases (PARPs) and glycohydrolase (PARG) are the key set of enzymes that orchestrate the rise and fall in cellular levels of poly(ADP-ribose). In this perspective, we focus on recent structural and mechanistic insights into the enzymes involved in poly(ADP-ribose) production and turnover, and we highlight important questions that remain to be answered.


Sex Hormone-Dependent Trna Halves Enhance Cell Proliferation In Breast And Prostate Cancers., Shozo Honda, Phillipe Loher, Megumi Shigematsu, Juan P. Palazzo, Ryusuke Suzuki, Issei Imoto, Isidore Rigoutsos, Yohei Kirino, Phd Jul 2015

Sex Hormone-Dependent Trna Halves Enhance Cell Proliferation In Breast And Prostate Cancers., Shozo Honda, Phillipe Loher, Megumi Shigematsu, Juan P. Palazzo, Ryusuke Suzuki, Issei Imoto, Isidore Rigoutsos, Yohei Kirino, Phd

Computational Medicine Center Faculty Papers

Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA-derived RNAs (SHOT-RNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER(-) breast cancer, AR(-) prostate cancer, or other examined cancer cell lines from other tissues. ER-dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. …


Diversification Of Importin-Α Isoforms In Cellular Trafficking And Disease States., Ruth A. Pumroy, Gino Cingolani Feb 2015

Diversification Of Importin-Α Isoforms In Cellular Trafficking And Disease States., Ruth A. Pumroy, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific …


Disrupting Sumoylation Enhances Transcriptional Function And Ameliorates Polyglutamine Androgen Receptor-Mediated Disease., Jason P Chua, Satya L Reddy, Zhigang Yu, Elisa Giorgetti, Heather L Montie, Sarmistha Mukherjee, Jake Higgins, Richard C Mceachin, Diane M Robins, Diane E Merry, Jorge A Iñiguez-Lluhí, Andrew P Lieberman Feb 2015

Disrupting Sumoylation Enhances Transcriptional Function And Ameliorates Polyglutamine Androgen Receptor-Mediated Disease., Jason P Chua, Satya L Reddy, Zhigang Yu, Elisa Giorgetti, Heather L Montie, Sarmistha Mukherjee, Jake Higgins, Richard C Mceachin, Diane M Robins, Diane E Merry, Jorge A Iñiguez-Lluhí, Andrew P Lieberman

Department of Biochemistry and Molecular Biology Faculty Papers

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that …