Associate Professor of Pharmacology & Toxicology and
Adjunct Associate Professor of Biochemistry and of Biomedical Informatics
B.A. University of California, San Diego
Ph.D. University of California, San Diego
Don Blumenthal's Lab Page
Don Blumenthal's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Protein Kinases, Acetylcholinesterase
My laboratory is broadly interested in the enzymes known as protein kinases and their roles in cell function and disease. Protein kinases catalyze the phosphorylation of proteins on serine, threonine, and tyrosine residues, which is the most common mechanism for the reversible covalent modification of protein structure and function. Protein kinases are the largest enzyme superfamily in eukaryotes, with more than 500 genes in the human genome. Many protein kinases are directly or indirectly involved in a variety of disease processes including cancer, diabetes, and heart disease, and there are now many drugs that target protein kinases and provide therapies for these diseases.
The protein kinases studied by my laboratory include the cAMP-dependent protein kinase (also known as protein kinase A or PKA), cGMP-dependent protein kinase (PKG), myosin light chain kinase (MLCK), phosphorylase kinase, and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. These protein kinases have very different subunit structures and are regulated in very different ways, even though their catalytic domains are homologous. Our research ranges from biochemical and biophysical studies of protein kinase structure and function, to studies of protein kinase activity in different disease states.
Much of our current basic research efforts are directed towards biophysical studies of protein kinases using fluorescence, circular dichroism (CD), small-angle x-ray (SAXS) and neutron scattering (SANS), and molecular dynamics (MD). We are using these methods to better understand the large-scale dynamic properties of protein kinases and their role in protein kinase function.
We have also recently begun to study a different enzyme, human acetylcholinesterase, the enzyme that hydrolyzes the neurotransmitter acetylcholine. This enzyme is the target of nerve gas agents and several drugs that have therapeutic application in treating glaucoma and Alzheimer's disease. We are interested in developing better antidotes to inhibitors of this enzyme by studying the conformational dynamics of the protein using techniques such as SAXS, MD simulations, and neutron and X-ray diffraction.
Figure: SAXS/SANS-based Models of PKA RIIbeta Holoenzyme (Blumenthal et al., J Biol Chem 2014)
- Bruystens JG, Wu J, Fortezzo A, Del Rio J, Nielsen C, Blumenthal DK, Rock R, Stefan E, Taylor SS. (2016) Structure of a PKA RIα Recurrent Acrodysostosis Mutant Explains Defective cAMP-Dependent Activation. Journal of Molecular Biology 428(24 Pt B):4890-4904
Kovalevsky A, Blumenthal DK, Cheng X, Taylor P, Radić Z. (2016) Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning. Annals of the New York Academy of Sciences 1378(1):41-49
- González Bardeci N, Caramelo JJ, Blumenthal DK, Rinaldi J, Rossi S, Moreno S. (2016) The PKA regulatory subunit from yeast forms a homotetramer: Low-resolution structure of the N-terminal oligomerization domain. J Struct Biol 193(2):141-54
- Kwon SH, Li L, He Y, Tey JC, Li H, Zhuplatov I, Kim SJ, Terry CM, Blumenthal DK, Shiu YT, Cheung AK. (2015) Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor. J Vasc Res 52(4):244-56
- Blumenthal DK, Copps J, Smith-Nguyen EV, Zhang P, Heller WT, Taylor SS. (2014) The roles of the RIIβ linker and N-terminal cyclic nucleotide-binding domain in determining the unique structures of the type IIβ protein kinase A: a small angle x-ray and neutron scattering study. J Biol Chem 289(41):28505-12
- Bruystens JG, Wu J, Fortezzo A, Kornev AP, Blumenthal DK, Taylor SS. (2014) PKA RIα homodimer structure reveals an intermolecular interface with implications for cooperative cAMP binding and Carney complex disease. Structure 22(1):59-69
- Sastri M, Haushalter KJ, Panneerselvam M, Chang P, Fridolfsson H, Finley JC, Ng D, Schilling JM, Miyanohara A, Day ME, Hakozaki H, Petrosyan S, Koller A, King CC, Darshi M, Blumenthal DK, Ali SS, Roth DM, Patel HH, Taylor SS. (2013) A kinase interacting protein (AKIP1) is a key regulator of cardiac stress. Proc Natl Acad Sci U S A 110(5):E387-96
- Ilouz R, Bubis J, Wu J, Yim YY, Deal MS, Kornev AP, Ma Y, Blumenthal DK, Taylor SS. (2012) Localization and quaternary structure of the PKA RIβ holoenzyme. Proc Natl Acad Sci U S A 109(31):12443-8
- Boettcher AJ, Wu J, Kim C, Yang J, Bruystens J, Cheung N, Pennypacker JK, Blumenthal DK, Kornev AP, Taylor SS (2011) Realizing the Allosteric Potential of the Tetrameric Protein Kinase A RIa Structure 19:265-76
- Jamros MA, Oliveira LC, Whitford PC, Onuchic JN, Adams JA, Blumenthal DK, Jennings PA (2010) Proteins at Work: A Combined SAXS and Theoretical Determination of the Multiple Structures Involved on the Protein Kinase Functional Landscape. J Biol Chem 285:36121-8
- Cheng CY, Yang J, Taylor SS, Blumenthal DK (2009) Sensing Domain Dynamics in PKA-RIa Complexes by Solution X-ray Scattering. J Biol Chem 284:35916-35925
- Tsalkova T, Blumenthal DK, Mei FC, White MA, Cheng X (2009) Mechanism of Epac Activation: Structural and Functional Analyses of Epac2 Hinge Mutants with Constitutive and Reduced Activities. J Biol Chem 284:23644-23651