Institute of Molecular Biology

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Brad Nolen

Brad Nolen

Associate professor, Chemistry and Biochemistry
Member, IMB

Ph.D., U.C. San Diego
B.S., Missouri State University

Lab website
Office: Klamath Hall Room 293
Office Phone: 541-346-7412

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Research Interests

The Nolen lab is investigating the molecular basis for regulation of the cytoskeleton, the molecular framework that provides physical support for cells. One of our primary interests is actin, a highly conserved eukaryotic protein which polymerizes into two-stranded helical filaments. Rearrangements of the actin filament network are critical for cellular processes that require a change in cell shape, such as motility, uptake and release of materials and cell division. To regulate these processes, cells utilize a myriad of proteins to control polymerization, depolymerization, severing, capping and crosslinking of actin filaments.

Actin filaments are generated de novo by actin nucleator proteins, which bring the first few actin monomers together to form a template for filament elongation. Arp2/3 complex, a 225kD assembly of seven subunits (Arp3, Arp2, ARPC1-5) is one such nucleator. Arp2/3 complex is intrinsically inactive, and activation requires binding to an activator, such as a WASp/Scar family protein, and recruitment of the complex to the side of a pre-existing actin filament. Once activated, the complex nucleates the growth of a new filament which is anchored to the pre-existing filament at a 78˚ angle. This process results in the formation of tightly crosslinked, highly branched filament networks.

nolen research Surface representation of the x-ray crystal structure of inactive Arp2/3 complex from Bos taurus.

Arp2/3 complex is essential in the formation of invadopdia, cellular structures essential for the migration of tumor cells through the basal lamina into the blood stream. Invading bacterial and viral pathogens usurp Arp2/3 complex in host cells to escape detection by the immune system. Despite the biomedical importance of the complex, many fundamental questions about how it functions remain unanswered. For instance, how do activator proteins like WASp/Scar activate Arp2/3 complex? How is the proposed activating conformational change accomplished and how does this change promote formation of the filament nucleus?

We use a combination of biochemistry, biophysics, x-ray crystallography and molecular dynamics simulations to investigate these questions, and our ultimate goal is to understand how phenomena observed at the cellular level are controlled at the molecular level. Therefore, we are especially interested in experimental systems in which we can test our findings in vivo. Schizosaccharomyces pombe provides one such system, since it is genetically tractable, can be used for production of the large quantities of protein required for x-ray crystallography and is suitable for microscopy.

Recent publications

(pulled from pubmed)

Recent publications

(pulled from pubmed)

Structural basis for regulation of Arp2/3 complex by GMF.
Luan Q, Nolen BJ
Nat Struct Mol Biol 2013 Sep;20(9):1062-8
Dip1 defines a class of Arp2/3 complex activators that function without preformed actin filaments.
Wagner AR, Luan Q, Liu SL, Nolen BJ
Curr Biol 2013 Oct 21;23(20):1990-8
Mechanism of a concentration-dependent switch between activation and inhibition of Arp2/3 complex by coronin.
Liu SL, Needham KM, May JR, Nolen BJ
J Biol Chem 2011 May 13;286(19):17039-46
Structural and biochemical characterization of two binding sites for nucleation-promoting factor WASp-VCA on Arp2/3 complex.
Ti SC, Jurgenson CT, Nolen BJ, Pollard TD
Proc Natl Acad Sci U S A 2011 Aug 16;108(33):E463-71
Incompatibility with formin Cdc12p prevents human profilin from substituting for fission yeast profilin: insights from crystal structures of fission yeast profilin.
Ezezika OC, Younger NS, Lu J, Kaiser DA, Corbin ZA, Nolen BJ, Kovar DR, Pollard TD
J Biol Chem 2009 Jan 23;284(4):2088-97
Characterization of two classes of small molecule inhibitors of Arp2/3 complex.
Nolen BJ, Tomasevic N, Russell A, Pierce DW, Jia Z, McCormick CD, Hartman J, Sakowicz R, Pollard TD
Nature 2009 Aug 20;460(7258):1031-4
Crystal structures of actin-related protein 2/3 complex with bound ATP or ADP.
Nolen BJ, Littlefield RS, Pollard TD
Proc Natl Acad Sci U S A 2004 Nov 2;101(44):15627-32