John M Rosenberg

My research philosophy is to bring a physical, problem-ori­ented ap­proach to the acquisition and interpretation of biomolecular structural information.   I view biological molecules as amazing machines that have reached the ultimate miniaturization possible in a universe composed of atoms and molecules; my approach is to pick interesting examples where it appears possible to develop understanding of how they work.

For example, my lab is studying α-synuclein, a neurologically important, natively unfolded protein implicated in a class of neurodegenerative diseases, such as Parkinson’s disease.  They are termed synuclienopathies because they are characterized by deposits containing large amounts of α-synuclein.  Exciting progress includes the crystallization of a GST- α-synuclein fusion protein; the crystals diffract to 2.2 Å resolution.  The GST portion has been localized by molecular replacement.  It is likely that most of the α-synuclein portion of the fusion protein is disordered and fills virtually all of the solvent channels implying solvent-like properties i.e. that α-synuclein can act as a macromolecular cosolvent, in addition to it’s other functions.  We are now exploring the hypothesis that α-synuclein can function physically in that role because of the obviously important biological implications.

Another project is in collaboration with Michael Grabe (Pitt), Jeffrey Abramson (UCLA), and Ernest Wright (UCLA).  We are applying computational methods to the group of membrane co-transporters that use a common structural motif known as a 5-helix inverted repeat; they have recently emerged as one of the largest structural classes of secondary transporters actively driving sugars, amino acids and neurotransmitters against an osmotic gradient; sodium gradients are a frequent energy source. We are focusing on the bacterial sugar transporter vSGLT as a model system to ask  questions including the following: 1. How do sodium and galactose interact during their release from their respective binding sites in the cytoplasmic-facing state of the protein? 2. How does water move through this transporter? Recent results include the observation that sodium must exit before sugar can enter the cytoplasm. We also observed that a significant amount of water penetrates the transporter through the sugar binding site. Our simulations suggest that water can passively permeate the transporter, and that sugar may also actively ‘pump’ water – a result that we are attempting to confirm now.