My lab studies the molecular machines involved in vesicular traffic, a fundamental process utilized by all compartmentalized cells from yeast to man to move proteins between different membranous compartments. Our initial interest in this subject grew out of our efforts to dissect the molecular mechanisms underlying synaptic transmission. We showed that the clathrin pathway is essential for synaptic vesicle recycling. We went on to characterize the mechanisms of clathrin polymerization and uncoating that underlie this process. The uncoating reaction is promoted by the chaperone protein Hsc70, which is a member of the Hsp70 family of chaperone proteins. These chaperone proteins are also involved in many aging related disorders that are a consequence of the accumulation of damaged, aggregated proteins (Alzheimer's, ALS, Parkinson's, Huntington's, and others). Therefore we are also interested in understanding the roles these chaperones play in both protein aggregation diseases and cancer during the aging process. We utilize a combination of biochemical and physiological approaches including solution biochemistry (surface plasmon resonance, dynamic light scattering, analytical ultracentrifugation, nuclear magnetic resonance spectroscopy), X-ray crystallography, and electrophysiology. Our work has broad significance since chaperones are involved in many macromolecular complex remodeling reactions.
Morgan JR, Jiang J, Oliphint PA, Jin S, Gimenez LE, Busch DJ, Foldes AE, Zhuo Y, Sousa R, Lafer EM. A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis. J Neurosci. 2013 May 1;33(18):8009-21.
Zhuo Y, Ilangovan U, Schirf V, Demeler B, Sousa R, Hinck AP, Lafer EM. Dynamic interactions between clathrin and locally structured elements in a disordered protein mediate clathrin lattice assembly. J Mol Biol. 2010 Nov 26;404(2):274-90.
Woo HJ, Jiang J, Lafer EM, Sousa R. ATP-induced conformational changes in Hsp70: molecular dynamics and experimental validation of an in silico predicted conformation. Biochemistry. 2009 Dec 8;48(48):11470-7.
Schuermann JP, Jiang J, Cuellar J, Llorca O, Wang L, Gimenez LE, Jin S, Taylor AB, Demeler B, Morano KA, Hart PJ, Valpuesta JM, Lafer EM, Sousa R. Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell. 2008 Jul 25;31(2):232-43.
Jiang J, Maes EG, Taylor AB, Wang L, Hinck AP, Lafer EM, Sousa R. Structural basis of J cochaperone binding and regulation of Hsp70. Mol Cell. 2007 Nov 9;28(3):422-33.