Hassane Mchaourab, Ph.D.

Lab News

Molecular spies illuminate drug resistance proteins

Glue Grant to enhance study of membrane proteins

Capturing transporters in motion

Recent Publications

McHaourab HS, Lin YL, Spiller BW. Crystal structure of an activated variant of small heat shock protein Hsp16.5. Biochemistry. 2012 Jun 26;51(25):5105-12. PMID: 22670769

Mishra S, Stein RA, McHaourab HS. Cataract-linked γD-crystallin mutants have weak affinity to lens chaperones a-crystallins. FEBS Lett. 2012 Feb 17;586(4):330-6. PMID: 22289178

McDonald ET, Bortolus M, Koteiche HA, Mchaourab HS. Sequence, structure, and dynamic determinants of Hsp27 (HspB1) equilibrium dissociation are encoded by the N-terminal domain. Biochemistry. 2012 Feb 14;51(6):1257-68. PMID: 22264079

McHaourab HS, Steed PR, Kazmier K. Toward the fourth dimension of membrane protein structure: insight into dynamics from spin-labeling EPR spectroscopy.
Structure. 2011 Nov 9;19(11):1549-61. PMID: 22078555

Mushrush DJ, Koteiche HA, Sammons MA, Link AJ, McHaourab HS, Lacy DB. Studies of the mechanistic details of the pH-dependent association of botulinum neurotoxin with membranes. J Biol Chem. 2011 Jul 29;286(30):27011-8. PMID: 21652698

Hoffman L, Stein RA, Colbran RJ, McHaourab HS. Conformational changes underlying calcium/calmodulin-dependent protein kinase II activation.. EMBO J. 2011 Apr 6;30(7):1251-62. PMID: 21343908

Kazmier K, Alexander NS, Meiler J, Mchaourab HS. Algorithm for selection of optimized EPR distance restraints for de novo protein structure determination.. J Struct Biol. 2011 Mar;173(3):549-57. PMID: 21074624

Claxton DP, Quick M, Shi L, de Carvalho FD, Weinstein H, Javitch JA, Mchaourab HS. Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters.. Nat Struct Mol Biol. 2010 Jun 20. PMID: 20562855

Amadi ST, Koteiche HA, Mishra S, Mchaourab HS. Structure, dynamics and substrate-induced conformational changes of the multidrug transporter EmrE in liposomes.. J Biol Chem. 2010 Jun 15. PMID: 20551331

Zou P, Mchaourab HS. Increased sensitivity and extended range of distance measurements in spin-labeled membrane proteins: Q-band double electron-electron resonance and nanoscale bilayers.. Biophys J. 2010 Mar 17;98(6):L18-20.

Gustot A, Smriti, Ruysschaert JM, Mchaourab H, Govaerts C. Lipid composition regulates the orientation of transmembrane helices in HorA, an ABC multidrug transporter. J Biol Chem. 2010 May 7;285(19):14144-51..

Zou P, Mchaourab HS. Alternating Access of the Putative Substrate-Binding Chamber in the ABC Transporter MsbA. J Mol Biol. 2009 Aug 25.

Zou P, Bortolus M, Mchaourab HS. Conformational Cycle of the ABC transporter MsbA in Liposomes. Detailed Analysis using Double Electron-Electron Resonance Spectroscopy. J Mol Biol. 2009 Aug 25.

Mchaourab H, Godar J, Stewart P. Structure and mechanism of protein stability sensors: The chaperone activity of small heat-shock proteins. Biochemistry. 2009 Mar 26.

Smriti, Zou P, Mchaourab HS .Mapping daunorubicin binding sites in the ABC transporter MsbA using site-specific quenching by spin labels. J Biol Chem. 2009 Mar 11.

Latham JC, Stein RA, Bornhop DJ, Mchaourab HS. Free-Solution Label-Free Detection of alpha-Crystallin Chaperone Interactions by Back-Scattering Interferometry. Analytical Chemistry 2009 Jan 29.

Hassane S. Mchaourab, Ph.D.

Professor of Molecular Physiology & Biophysics
Professor of Physics & Chemistry
Vanderbilt University Medical Center

Dynamics represent the fourth dimension linking protein structures to mechanisms. Proteins have parts that gate, bend, twist or catalyze a given reaction. These dynamic transitions take place on time scales ranging from picosecond side chain rotameric equilibria to millisecond rearrangements in cooperative protein complexes. Despite spectacular recent progress, the study of dynamics of membrane proteins and macromolecular complexes remain an immature area of research.

The main experimental focus in my laboratory is to understand the dynamic dimension of protein structures. We have developed and applied spectroscopic approaches based on paramagnetic or fluorescent reporter groups to characterize the collective functional or regulatory motion of protein secondary structures and domains. Highlights of our work include describing protein motion that coupling ATP hydrolysis to substrate translocation by transporters, hinge motion in T4 Lysozme, and single molecule detection of domain movement.

We use spin labeling with EPR spectroscopy as our major experimental tool to describe protein dynamics in energy transduction systems for signaling, energy conversion systems for transport, and stability sensors for conformational editing. We seek to define the energy transduction events converting various stimuli into protein motion and to determine the structure of end point states. Spin labeling also allows analysis of well-defined biochemical intermediates in native-like environments without the conformational selectivity imposed by lattice forces.

Current topics of interests include:

Molecular aspects of protein aggregation in aging and disease: Structure and function of heat shock proteins, structure of amyloids.

Multidrug resistance in cancer and infectious diseases: Structural basis of substrate recognition and translocation for the bacterial lipid flippase MsbA, human multidrug resistance protein (p-glycoprotein) and the bacterial multidrug transporter EmrE.

Neurotransmitter transporters: Dissection of the transport cycle for bacterial homologs of the dopamine and serotonin transporters in collaboration with the Jonathan Javitch lab at Columbia University.

CamKII Kinase: Structural basis of regulation and motifs of protein-protein interactions in collaboration with the Roger Colbran Lab at Vanderbilt University.