Ralf Langen
Professor,
Dept. of Biochemistry & Molecular Biology
Zilkha Neurogenetic Institute
Keck School of Medicine
Research Topics
- Structural Biology and Biophysics
- Protein Misfolding and Amyloid Diseases
- Membrane Protein Structure and Function
Research Overview
Our main interests lie in the basic areas of protein folding and misfolding, and particular emphasis is placed on these processes when they occur on or around membranes. The interaction of proteins with membranes underlies many important biological processes. Proteins can regulate the structure and function of biological membranes by controlling the composition, fluidity, permeability and curvature of cellular membranes. Membranes, in turn, can have a pronounced effect on the structure and function of proteins and help to promote physiologically important structural reorganizations of proteins. In addition, membrane interaction can also result in protein misfolding which could ultimately cause disease. We investigates the interaction between proteins and membranes in three biological contexts:1) Reversible membrane insertion of soluble proteins. We would like to understand the general molecular mechanisms that enable soluble proteins to insert into membranes and form ion channels. Our model system for membrane insertion is annexin XII, a soluble protein that, as we discovered, is also capable of reversibly inserting into membranes and forming ion channels.
2) Recognition and stabilization of membrane curvature. Although regulation of membrane curvature is a key event in many biological processes, including endocytosis, exocytosis and vesicle budding, it remains poorly understood. We are studying structural features that allow proteins to sense or stabilize membrane curvature in endocytosis.
3) Protein misfolding and amyloid fibril formation in disease. Recently, we have taken an interest in the areas of protein misfolding and amyloid fibril formation. We are particularly interested in protein misfolding as it pertains to Alzheimers disease, dementia, Parkinsons disease, type-2 diabetes and macular degeneration. It is our objective to understand how certain misfolded forms of amyloid proteins are able to insert into membranes and perturb membrane structure. Furthermore, we are investigating both the general molecular mechanisms that cause amyloid fibril formation and the manner by which this process is modulated by phospholipids.
Despite significant interest and biomedical relevance, it has proven difficult to address these questions using conventional high-resolution structural methods. We have therefore been applying a broad range of biophysical methods. To date, site-directed spin labeling (SDSL), in combination with electron paramagnetic resonance (EPR) spectroscopy, has been most instrumental in our endeavors. SDSL is a powerful new approach for the structural analysis of membrane proteins, and, as we recently found, amyloid fibrils. The basis of SDSL is to introduce a spin label into a given protein sequence. Through EPR analysis of multiple derivatized proteins, it is possible to determine local structure and dynamics, to map inter-residue distances, and, ultimately, to generate reliable three-dimensional structures.
Selected Publications
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Zhang, Q.C., Yeh, T.I, Levya, A., Frank, L.G., Miller, J., Kim, Y.E., Langen, R., Finkbeiner, S., Amzel, M.L., Ross, C.A., Poirier, M.A. A compact β model of huntingtin toxicity. (2011) Jan 5 [Epub ahead of print] -PubMed
Kim, Y.E., Chen, J., Langen, R., Chan,J.R., , Monitoring apoptosis and neuronaldegeneration by real-time detection of phosphatidylserine externalization usinga polarity sensitive indicator of viability and apoptosis (pSIVA). (2010) Nature Protocols, 5, 1396-405 -PubMed
Varkey, J., Isas, J.M., Mizuno, M., Jensen,M.B., Bhatia, V.K., Jao, C.C., Voss, J., Stamou, D. Steven, A.C., Langen, R. Membrane Curvature Inductionand Tubulation is a Common Feature of Synucleins and Apolipoproteins. (2010) J. Biol. Chem., 285, 32486-93 -PubMed
Kim, Y.E., Chen, J., Chan, J.R., Langen,R., Engineering a Polarity Sensitive Biosensor for Time-lapse Imaging of Apoptotic Processesand Degeneration. (2010) Nature Methods,7, 67-73.
Mizuno, N., Jao, C. J., Langen, R., Steven, A.C. Endophilin-mediated conversion of lipidvesicles into coated tubes of cylindrical, micellar and bulbous morphology.(2010) J.Biol.Chem., 285, 23351-8
-PubMed
Jao, C.C.,Hegde, B.G., Gallop, J.L., Peter, B.J., Hegde, P.B., McMahon, H.T., Haworth,I.S., Langen, R., Roles ofamphipathic helices in the BAR domain of endophilin in membrane curvaturegeneration. (2010) J.Biol. Chem., 285,20164-70.
Rao, J.N., Jao,C.C., Hegde, B.C., Langen, R.,Ulmer, T., A combinatorial NMR and EPRapproach for assessing the structural ensemble of partially folded proteins.(2010) J. Am. Chem. Soc., 132,8657-68
Wu, J., Breydo, L., Isas, J.M., Lee, J.,Kuznetsov, Y.G., Langen, R., Glabe, C.G. Fibrillar oligomers nucleate the oligomerizationof monomeric Aß, but do not seed fibril formation. (2010) J. Biol. Chem., 285, 6071-9
Ladner, C.L., Chen, M, Smith, D.P., Radford, S.E., Langen, R., Stackedsets of parallel, in register beta-strands of beta-2-microglobulin in amyloidfibrils revealed by site-directed spin labelling and chemical labelling.(2010) J.Biol. Chem., 285, 17137-47.
Daval, M., Bedrood, S., Gurlo, T., Huang, C.J.,Costes, S.,
Jao, C.C., Hegde, B.G., Chen, J., Haworth, I.S., Langen, R. Structure of Membrane-bound alpha-Synuclein from Site-directed Spin Labeling and Computational Refinement. (2008) Proc. Natl. Acad. Sci., 105, 19666-71
Margittai, M., Langen, R., Fibrils with Parallel in-register Structure Constitute a Major Class of Amyloid Fibrils: Molecular Insights from electron paramagnetic resonance spectroscopy. (2008) Quarterly Reviews of Biophysics, 41, 265-97
Apostolidou, M., Jayasinghe, S., Langen, R., Structure of alpha-helical Membrane-bound hIAPP and its Implications for Membrane-mediated Misfolding. (2008) J. Biol. Chem., 283, 17205-17210
-PubMedHenne WM, Kent HM, Ford MG, Hegde BG, Daumke O, Butler PJ, Mittal R, Langen R, Evans PR, McMahon HT. - Structure and Analysis of FCHo2 F-BAR Domain: A Dimerizing and Membrane Recruitment Module that Effects Membrane Curvature. - Structure [ 2007 ] May 30; . PubMed
Chen M, Margittai M, Chen J, Langen R. - Investigation of alpha -synuclein fibril structure by site-directed spin labeling. - J Biol Chem [ 2007 ] Jun 15; . PubMed
Fischer T, Lu L, Haigler HT, Langen R. - Annexin B12 is a sensor of membrane curvature and undergoes major curvature-dependent structural changes. - J Biol Chem [ 2007 ] Mar 30;282(13):9996-10004 .
Margittai M, Langen R. - Side-chain-dependent stacking modulates tau filament structure. - J Biol Chem [ 2006 ] Oct 5; -PubMed
Gallop JL, Jao CC, Kent HM, Butler PJ, Evans PR, Langen R, McMahon HT. - Mechanism of endophilin N-BAR domain-mediated membrane curvature. - EMBO J [ 2006 ] Jun 21;25(12):2898-910 -PubMed
Luibl V, Isas JM, Kayed R, Glabe CG, Langen R, Chen J. - Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. - J Clin Invest [ 2006 ] Feb;116(2):378-85 . -PubMed
Jao, C.C., Der-Sarkissian, A., Chen, J., Langen, R. Structure of Membrane-Bound alpha-Synuclein Studied by Site-Directed Spin Labeling. (2004) Proc. Natl. Acad. Sci. USA, 101, 8331-8336
Margittai, M., Langen, R. Template-Assisted Filament Growth by Parallel Stacking of Tau. (2004) Proc. Natl. Acad. Sci. USA, 101, 10278-10283
