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Integrative Structural and Computational Biology

Ronald A. Milligan, Ph.D.

Professor
Department of Integrative Structural and Computational Biology
California Campus
Laboratory Website
milligan@scripps.edu
(858) 784-9827

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Structure and Action of Molecular Machines

In cells there are hundreds of macromolecular assemblies. They may be composed of only a few or perhaps scores of proteins and are the functional units - the molecular machines - of the cell. We use cryo-electron microscopy and image analysis to study the structure and mechanism of action of several of these molecular machines. The three-dimensional maps we calculate from electron images of the assemblies are used together with the x-ray structures of the individual components to build models of the working machines and to understand their molecular mechanisms. We have ongoing research projects on the following assemblies: actomyosin, kinesin-microtubules, MAPs-microtubles, VCP/p97 and dynein AAA ATPases, various membrane channels and transporters, bacterial toxins.

Education

Ph.D., Stanford University, 1985

Awards & Professional Activities

Editorial Board, Journal Structural Biology;
Member: Science and Society Institute of the Pew Scholars Program in the Biomedical Sciences

Selected References

Mulder, A.M., Yoshioka, C., Beck, A.H.,  Bunner, A.E., Milligan, R.A., Potter, C.S., Carragher, B. and Williamson, J.R.   Visualizing ribosome biogenesis: parallel assembly pathways for the 30S subunit. Science 330:673-677, 2010.   PMCID: PMC2990404

Subramanian, R., Wilson-Kubalek, E.M.,  Arthur, C.P.,  Bick, M.J., Campbell, E.A., Darst, S.A., Milligan, R.A. and Kapoor, T.M.  Insights into antiparallel microtubule crosslinking by PRC1, a conserved nonmotor microtubule binding protein.  Cell 142:433-443, 2010.   PMCID: PMC2966277

Mulder, A., Glavis-Bloom, A.,  Moores, C.A., Wagenbach, M., Carragher, B., Wordeman, L. and Milligan, R.A.  A new model for binding of kinesin 13 to curved microtubule protofilaments.  J. Cell Biol. 185:51-57, 2009.   PMCID: PMC2700504

Ward, A.,  Mulligan, S., Carragher, B., Chang, G. and Milligan, R.A.   Nucleotide dependent packing differences in helical crystals of the ABC transporter MsbA.  J. Struct. Biol. 165:169-175, 2009.  PMCID: PMC2703300

Carter, A.P.,  Garbarino, J.E., Wilson-Kubalek, E.M., Shipley, W.E., Cho, C., Milligan, R.A., Vale, R.D. and Gibbons, I.R. Structure and Functional Role of Dynein’s Microtubule-Binding Domain, 2008.  Science  322:1691-1695. PMCID: PMC2663340

Wilson-Kubalek, E.W., Cheeseman, I.M., Yoshioka, C., Desai, A. and Milligan, R.A.  Orientation and structure of the Ndc80 complex on the microtubule lattice.  J. Cell Biol. 182:1055-1061, 2008.   PMCID: PMC2542468

Littlefield, K.P.,  Chappie, J.S., Ward, A.B., Reedy, M.K., Bernstein, S.I., Milligan, R.A. and Reedy, M.C.  Similarities and differences between frozen-hydrated, rigor acto-S1 complexes of insect flight and chicken skeletal muscles.  J. Mol. Biol.  381:519-528, 2008.  PMCID: PMC2567842 

Moores, C.A. and Milligan, R.A.  Visaulization of a kinesin-13 motor on microtubule end mimics.  J. Mol. Biol. 377:647-654, 2008.   PMCID: PMC2396873

Vale, R.D.,Milligan, R.A.. The way things move: Looking under the hood of molecular motor proteins. Science 288:88-95, 2000.

Moores, C.A., M. Yu, J. Guo, C. Beraud, R. Sakowicz and R.A. Milligan A mechanism for microtubule depolymerizatin by KinI kinesins. Molecular Cell 9:903-909, 2002.

Kazmierczak, P., Sakaguchi, H. Tokita, J., Wilson-Kubalek, E.M., Milligan, R.A., Müller, U., Kachar, B.  Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells.  Nature 449:87-91, 2007.  PMID: 17805295.

Yoshioka, C., Pulokas, J. Fellmann, D., Potter, C.S., Milligan, R.A., Carragher, B.  Automation of random conical tilt and orthogonal tilt data collection using feature-based correlation.  J. Struct. Biol. 159:335-346, 2007. PMCID: PMC2043090

Gregorini, M., Wang, J., Xie, X.-S., Milligan, R.A., Engel, A.   Three-dimensional reconstruction of bovine brain V-ATPase by cryo-electron microscopy and single particle analysis.  J. Struct. Biol. 158:445-454, 2007.

Al-Bassam, J., Roger, B., Halpain, S., Milligan, R.A.  Analysis of the weak interactions of ADP-Unc104 and ADP-kinesin with microtubules and their inhibition by MAP2c.  Cell Motil. Cytoskel. 64:377-389, 2007. PMID: 17326138 

Neuman, B.W., Adair, B.D., Yoshioka, C., Quispe, J.D., Milligan, R.A., Yeager M., Buchmeier, M.J.  Ultrastructure of SARS-CoV, FIPV, and MHV revealed by electron cryomicroscopy.  Adv. Exp. Med. Biol. 581:181-185, 2006.

Moores, C.A., Milligan, R.A.  Lucky 13-microtubule depolymerization by kinesin-13 motors.  J. Cell Sci. 119:3905-3913, 2006.

Moores, C.A., Cooper, J., Wagenbach, M., Ovechkina, Y., Wordeman, L., Milligan, R.A.  The role of the kinesin-13 neck in microtubule depolymerization.  Cell Cycle 5:1812-1815, 2006.

Neuman, B.W., Adair, B.D., Yoshioka, C., Quispe, J.D., Orca, G., Kuhn, P., Milligan, R.A., Yeager, M., Buchmeier, M.J.  Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopyJ. Virol.  80:7918-7928, 2006

Endres, N.F., Yoshioka, C., Milligan, R.A., Vale, R.D.  A lever arm rotation drives motility of the minus-end-directed kinesin, Ncd.  Nature 439:875-878, 2006.

Dang, T.X., Milligan, R.A., Tweten, R.K., Wilson-Kubalek, E.M.  Helical crystallization on nickel–lipid nanotubes: Perfringolysin O as a model protein.  J Struct Biol. 152:129-139, 2005.

Manuell, A.L., Yamaguchi, K., Haynes, P.A., Milligan, R.A., Mayfield, S.P. Composition and structure of the 80S ribosome from the green alga Chlamydomonas reinhardtii: 80S ribosomes are conserved in plants and animals. J. Mol. Biol. 351:266-279, 2005.

Neuman, B., Adair, B.D., Burns, J.M., Milligan, R.A., Buchmeier, M.J., Yeager, M.  Complementarity in the supramolecular design of arenaviruses and retroviruses revealed by electron cryo-microscopy and image analysis.  J. Virol. 79:3822-3830, 2005.

O’Keefe, M.A., Turner, J.H., Musante, J.A., Jetherington, C.J.D., Cullis, A.G.,  Carragher, B., Junnkins, R., Milgrim, J., Milligan, R.A., Potter, C.S., Allard, L.F., Bloom, D.A., Degenhardt, L., Sides, W.H.  Laboratory design for high performance electron microscopy.  Microscopy Today 12:8-14, 2004.

Moores, C.A., Perderiset, M., Francis, F., Chelly, J., Houdusse, A., Milligan, R.A. Mechanism of microtubule stabilization by doublecortin. Molecular Cell 14:833-839, 2004.

Roger, B., Al-Bassam, J., Dehmelt, L., Milligan, R.A., Halpain, S.  MAP2c, but not tau, binds and bundles F-actin via its microtubule binding domainCurr. Biol.  14:363-371, 2004.  

Carragher, B., Fellman, D., Guerra, F., Milligan, R.A., Mouche, F., Pulokas, J., Sheehan, B., Quispe, J., Suloway, C., Zhu, Y., Potter, C.  Rapid routine structure determination of macromolecular assemblies using electron microscopy: current progress and further challenges.  J. Synchrotron Radiat. 11:83-85, 2004.

Batters, C., Arthur, C.P., Lin, A., Porter, J., Geeves, M.A., Milligan, R.A., Molloy, J.E., Colucccio, L.M.  Myo1c is designed for the adaptation response in the inner ear.  EMBO J. 23:1433-1440, 2004.

Shipley, K., Hekmat-Nejad, M., Turner, J., Moores, C., Anderson, R., Milligan, R., Sakowicz, R., Fletterick, R.  Structure of a kinesin microtubule depolymerization machine.  EMBO J. 23:1422-1432, 2004. 

Moores, C.A., Hekmat-Nejad, M., Sakowicz, R., Milligan, R.A.  Regulation of KinI kinesin ATPase activity by binding to the microtubule lattice.  J. Cell Biol. 163:963-971, 2003.

Ward, A., Moody, M.F., Sheehan, B., Milligan, R.A., Carragher, B.  Windex: A toolset for indexing helices.  J. Struct. Biol. 144:172-183, 2003.

Al-Bassam, J., Cui, Y., Klopfenstein, D., Carragher, B.O., Vale, R.D., Milligan, R.A.  Distinct conformations of the kinesin unc104 neck regulate a monomer to dimer motor transition.  J. Cell Biol. 163:743-753, 2003.

Hinshaw, J.E., Milligan, R.A.  Nuclear pore complexes exceeding eightfold  rotational symmetry.  J. Struct. Biol. 141:259-268, 2003. 

Rouiller, I., DeLaBarre, B., May, A.P., Weiss, W.I., Brunger, A.T., Milligan, R.A., Wilson-Kubalek, E.M.  Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle.  Nature Struct. Biol. 9:950-957, 2002.

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