Protein Regulation, Structure, and Dynamics
We study the fundamental mechanisms by which signaling proteins are activated and inhibited: protein-protein interactions, localization, and energetic constraints. We have used structure, biophysics and structure-guided mutagenesis to test questions about protein dynamics, allosteric regulation, and dimer formation in membrane-proximal signaling proteins.
Most recently, we are investigating the role of dimerization in the tyrosine kinase Csk, the master negative regulator of the Src-family kinases.
Select Publications
A dominant function of LynB kinase in preventing autoimmunity
Brian*, Sauer*, Greene* (co-first), Senevirathne, Lindstedt, Funk, Ruis, Ramirez, Auger, Swanson, Nunez, Moriarity, Lowell, Binstadt, Freedman
(2022) Sci Adv. 8(16):eabj5227. PMID:35452291
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Brian, Sjaastad, Freedman (2022) Sci Rep. 12:5875. PMID:35393453
Regulation of myeloid-cell activation (review)
Greene, Brian, Senevirathne, Freedman (2021) Curr Opin Immunol. 73:34-42. PMID:34601225
The Src-family kinase Lyn in immunoreceptor signaling (review)
Brian, Freedman (2021) Endocrinology. 162(10):bqab152. PMID:34320188
Immunopharmacology and quantitative analysis of tyrosine kinase signaling (review/protocol)
Brian, Guerrero, Freedman (2020) Curr Protoc Immunol. 130(1):e104. PMID:32931655
Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
Brian, Jolicoeur, Guerrero, Nunez, Sychev, Hegre, Sætrom, Habib, Drake, Schwertfeger, Freedman (2019) eLife. 8:e46043. PMID:31282857
LynA regulates an inflammation-sensitive signaling checkpoint in macrophages
Freedman (co-corresponding), Tan, Skrzypczynska, Manz, Sjaastad, Goodridge, Lowell, Weiss (2015) eLife. 4:e09183. PMID:26517880
STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development
Limnander, Depeille, Freedman, Liou, Leitges, Kurosaki, Roose, Weiss (2011) Nat Immunol. 12(5): 425-433. PMID:21441934
ZAP-70: an essential kinase in T-cell signaling (review)
Wang, Kadlecek, Au-Yeung, Goodfellow, Hsu, Freedman, Weiss (2010) Cold Spring Harb Perspect Biol. 2:a002279. PMID:20452964
Differences in flexibility underlie functional differences in the Ras activators Son of sevenless and Ras guanine nucleotide releasing factor 1
Freedman, Sondermann, Kuchment, Friedland, Kortemme, Kuriyan (2009) Structure. 17(1):41-53. PMID:19141281
A Ras-induced conformational switch in the Ras activator Son of sevenless
Freedman, Sondermann, Friedland, Kortemme, Bar-Sagi, Marqusee, Kuriyan (2006) Proc Natl Acad Sci USA. 103(45):16692-16697. PMID:17075039
Structural analysis of the inactive state of the Escherichia coli DNA polymerase clamp-loader complex
Kazmirski, Podobnik, Weitze [=Freedman], O'Donnell, Kuriyan (2004) Proc Natl Acad Sci USA. 101(48):16750-16755. PMID:15556993
Nucleotide-induced conformational changes in an isolated Escherichia coli DNA polymerase III clamp loader subunit
Podobnik, Weitze [=Freedman], O'Donnell, Kuriyan (2003) Structure. 11(3):253-263. PMID:12623013