Wayne L. Hubbell

Professor of Biochemistry and Jules Stein Professor of Ophthalmology


BS, Oregon State University; PhD., Stanford University; AFORSR-NRC Postdoctoral Fellow, Chemistry, Stanford University; Alfred P. Sloan Foundation Fellow; Camille and Henry Dreyfus Foundation Teacher-Scholar Award; Research to Prevent Blindness Senior Investigator Award; NIH MERIT Award; Biophysical Society's Elisabeth Roberts Cole Award; Alexander M. Cruickshank Lecturer; Honorary Degree, University of Pécs, Hungary; Fellow of the Biophysical Society; Gold Medal, International EPR Society; Fellow, American Academy of Arts and Sciences; Associate Director of Jules Stein Eye Institute; Member of UCLA Molecular Biology Institute; Member of UCLA Brain Research Institute; Member of California Nano Systems Institute.

Phone: (310) 206-8830
Fax: (310) 794-2144

E-mail:hubbellw@jsei.ucla.edu

Jules Stein Eye Institute
UCLA School of Medicine
100 Stein Plaza
Los Angeles, CA 90095-7008

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 Current Research

Dr. Hubbell's research is focused on understanding the relationship between the molecular structure of a protein and the conformational changes that control its function. Of particular interest are membrane proteins that behave as "molecular switches", i.e., proteins whose structures are switched to an active state by a physical or chemical signal. A primary example under study is light-activated rhodopsin, the visual pigment in photoreceptor cells of the retina. The goal is to elucidate the structure of rhodopsin, the mechanism of the molecular switch, and regulation of this switch by associated proteins, transducin and arrestin. Recently, his research has broadened to include structure/function relationships in water soluble proteins such as the lens protein, a-crystallin and the family of retinoid carrying proteins that transport vitamin A throughout photoreceptor cells.

To investigate these proteins, Dr. Hubbell's laboratory has developed the technique of site-directed spin labeling (SDSL), a novel and powerful approach to the exploration of protein structure and dynamics. By changing the genetic code, a specific attachment point in the protein is created for a nitroxide spin label probe. Analysis of the electron paramagnetic resonance (EPR) spectrum of the spin label provides a wealth of information about the local environment in the protein. With a sufficiently large set of labeled proteins, global information on structure is obtained, and most importantly, changes in the structure during function can be followed in real time.

 Representative Publications

Molecular motion in spin-labeled phospholipids and membranes. W.L. Hubbell and H.M. McConnell J. Am. Chem. Soc. 93:314 (1971) (Cited by Current Contents as a citation index classic.)

Site-directed mutagenesis of colicin E1 provides specific attachment sites for spin labels whose spectra are sensitive to local conformation. A. Todd, V. Crozel, F. Levinthal, C. Levinthal and W. Hubbell Proteins: Struct. Funct. Genet. 6:294 (1989)

A transbilayer coupling mechanism for the formation of lipid asymmetry in biological membranes. Application to photoreceptor disc membranes. W. Hubbell Biophys. J. 57:99-108 (1990).

A method to determine transmembrane protein structure: spin-labeling of bacteriorhodopsin mutants. C. Altenbach, T. Marti, H. Khorana, and W. Hubbell Science 248: 1088 (1990)

Advances in spin label oximetry. J. Hyde, J. Yin, J. Feix, W. Hubbell Pure Appl. Chem. 62:255-260 (1990).

Molecular characterization of helix-loop-helix peptides. S. Anthony-Cahill, P. Benfield, R. Fairman, Z. Wasserman, S. Brenner, C. Altenbach, W. Hubbell, W. Stafford, W. DeGrado Science 255:979 (1992)

Colicin E1 binding to membranes: time-resolved studies of spin-labeled mutants. Y. Shin, C. Levinthal, F. Levinthal, W. Hubbell, Science 259:960-63 (1993)

Photoactivated conformational changes in rhodopsin: a time-resolved spin label study, Z. Farahbakhsh, K. Hideg, Hubbell WL, Science 262:1416-1420 (1993)

A collision gradient method to determine the immersion depth of nitroxides in lipid bilayers: application to spin labeled mutants of bacteriorhodopsin C. Altenbach, D. Greenhalgh, H. Khorana, W. Hubbell, PNAS. 91:1667-71 (1994)

Site-specific incorporation of biophysical probes into proteins, V. Cornish, D. Bentson, C. Altenbach, K. Hideg, W. Hubbell, P. Schultz, Proc. Natl. Acad. Sci. 91:2910-14 (1994)

Time resolved detection of structural changes during the photocylce of spin labeled bR. H. Steinhoff, R. Mollaaghababa, C. Altenbach, K. Hideg, M. Krebs, H. Khorana, W. Hubbell, Science 266:105-107 (1994)

A method for distance determination in proteins using designed metal ion binding sites and site-directed spin labeling. J. Voss, L. Salwinski, H. R. Kaback, W. Hubbell, Proc. Natl. Acad. Sci. 92:12295-12299 (1995)

Motion of spin labeled side chains in T4 lysozyme. Correlation with protein structure and dynamics. H.S. Mchaourab, M. Lietzow, W. Hubbell, Biochemistry 35:7692-7704 (1996)

Calculation of EPR spectra from Brownian dynamics trajectories: application to nitroxide side-chains in proteins. H.-J. Steinhoff, W. Hubbell Biophys. J. 71:2201-2212 (1996).

Watching your protein move using site-directed spin labeling. W. Hubbell, H. Mchaourab, C. Altenbach, M. Lietzow. Structure 4:779-783 (1996).

Structural features and light-dependent changes in the cytoplasmic interhelical E-F loop in rhodopsin: a site-directed spin labeling study. C. Altenbach, K. Yang, D. Farrens, Z. Farahbakhsh, H.G. Khorana, W. Hubbell, Biochemistry 35:12470-12478 (1996).

Organization of diphtheria toxin T domain in bilayers: a site-directed spin labeling study. K.-J. Oh, H Zhan, C. Cui, K. Hideg, R.J. Collier, W. Hubbell, Science 273:810-812 (1996).

Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. D. Farrens, C. Altenbach, K. Yang, W. Hubbell, H.G. Khorana, Science 274:768-770 (1996).

Structure and function in rhodopsin. The proximity of cysteines 65 and 316 in a rhodopsin mutant assayed by disulfide formation and spin label interactions. K. Yang, D. Farrens, C. Altenbach, W. Hubbell, H.G. Khorana, Biochemistry 35:14040-14046 (1996).

Conformation of T4 lysozyme in solution. Hinge-bending motion and the substrate-induced conformational transition studied by site-directed spin labeling. H. Mchaourab, K.-J. Oh, C. Fang, W. Hubbell, Biochemistry 36:307-316 (1997).

Structure and function of rhodopsin: rhodopsin mutants with a neutral amino acid at E134 have a partially activated conformation in the dark. J.-M. Kim, C. Altenbach, R. Thurmond, H. G. Khorana, W.L. Hubbell Proc. Natl. Acad. Sci. 94:14273-14278 (1997).

Helix packing in the lactose permease determined by metal-nitroxide interaction. J. Voss, W. Hubbell, H.R. Kaback, Biochemistry 37:211-216 (1998).

Docking phospholipase A2 on membranes using electrostatic potential-modulated spin relaxation magnetic resonance. Y. Lin, R. Nielson, D. Murray, W. Hubbell, C. Mailer, B. Robinson, M. Gelb Science 279:1925-1929 (1998).

Membrane mediated assembly of annexins studied by site-directed spin labeling. R. Langen, J. Isas, H. Leuke, H. Haigler, W. Hubbell, J. Biol. Chem. 273:22453-22457 (1998).

A transmembrane form of annexin XII detected by site-directed spin labeling. R. Langen, M. Isas, W. Hubbell, H. Haigler, Proc. Natl. Acad. Sci. 95:14060-14065 (1998).

The structure of 402-424 region of membrane-bound pore-forming domain of colicin E1: a site-directed spin labeling study. Protein Sci. 8:562-572 (1999).

Motion of spin labeled side chains in T4 lysozyme: effect of side chain structure. H. Mchaourab, T. Kalai, K. Hideg, W. Hubbell, Biochemistry 38:2947-2955 (1999).

A multifrequency ESR study of T4 lysozyme dynamics. J. Barnes, Z. Liang, H. Mchaourab, J. Freed, W. Hubbell, Biophys. J. 76: 3298-3306 (1999).

Structural features of the C-terminal domain of bovine rhodopsin: a site-directed spin labeling study. R. Langen, K. Cai, C. Altenbach, H.G. Khorana, W. Hubbell, Biochemistry 38: 7918-7924 (1999).

Structural features and light-dependent in the sequence 306-322 extending from helix VII to the palmitoylation sites in rhodopsin: A site-directed spin labeling study. C. Altenbach, K. Cai, H.G. Khorana, W. Hubbell, Biochemistry 38: 7931-7937 (1999).

Structural features and light-dependent changes in the sequence 59-75 connecting helices I and II in rhodopsin: A site-directed spin labeling study. C. Altenbach, J. Klein-Seetharaman, H.G. Khorana, W.Hubbell, Biochemistry 38: 7945-7949 (1999).

Conformation of the diphtheria toxin T domain in membranes: A site-directed spin-labeling study of the TH8 helix and TL5 loop. K-J Oh, H. Zhan, Can Cui, C. Altenbach, W. Hubbell, R.J. Collier, Biochemistry, in press.

The structure of the KcsA potassium channel from Streptomyces lividans: a site-directed spin labeling study of the second transmembrane segment. A. Gross, L. Columbus, K. Hideg, C. Altenbach, W. Hubbell, Biochemistry 38:10324-10335 (1999).

Crystal structure of spin labeled T4 lysozyme mutants: implications for the interpretation of EPR spectra in terms of structure. R. Langen, K.-J. Oh, D. Cascio, W. Hubbell, Biochemistry 39:8396-8405 (2000).

Identifying conformational changes with site-directed spin labeling. W. Hubbell, D. Cafiso, C. Altenbach, Nature Struct. Biol. 7:735-739 (2000).

Molecular motion of spin labeled side chains in a-helices: analysis by variation of side chain structure. L. Columbus, T. Kalai, J. Jeko, K. Hideg, W. Hubbell, Biochemistry 40:3828-3846 (2001).

Quantitative analysis of the isolated GAAA tetraloop/receptor interaction in solution: A site-directed spin labeling study. P. Qin, S. Butcher, J. Feigon, W. Hubbell, Biochemistry 40: 6929-6936 (2001).

Estimation of inter-residue distances in spin labeled proteins at physiological temperatures: experimental strategies and practical limitations.C. Altenbach, K.-J. Oh, R. Trabanino, K. Hideg, W. Hubbell, Biochemistry 40: 15471-82 (2001).

Structure and dynamics of a helical hairpin and loop region in annexin 12: A site-directed spin labeling study. J. Isas, R. Langen, H. Haigler, and W. Hubbell Biochemistry 41: 1464-1473 (2002).

Identification of protein side chains near the membrane/aqueous interface: a site-directed spin labeling study of KcsA. A. Gross and W. Hubbell Biochemistry 41:1123-1128 (2002).

A new spin on protein dynamics. L. Columbus and W. Hubbell TiBS 27: 288-295 (2002).

 Current and Former Lab Members