Keck School Faculty

Ralf Langen

Ralf Langen

Professor of Physiology & Neuroscience
Director, Protein Structure Center, Zilkha Neurogenetic Institute
Director of the Ph.D. Program in Medical Physiology, Co-Director, Ph.D. Program in Medical Biophysics
Zilkha Neurogenetic Institute
ZNI 121, 1501 San Pablo Street Health Sciences Campus Los Angeles

The Dynamic Interactions of a Multitargeting Domain in Ameloblastin Protein with Amelogenin and Membrane Int J Mol Sci. 2023 Feb 09; 24(4). . View in PubMed

Molecular basis of Q-length selectivity for the MW1 antibody-huntingtin interaction J Biol Chem. 2023 04; 299(4):104616. . View in PubMed

Amplification of neurotoxic HTTex1 assemblies in human neurons Neurobiol Dis. 2021 11; 159:105517. . View in PubMed

Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted Nat Commun. 2021 07 13; 12(1):4272. . View in PubMed

Lysine acetylation regulates the interaction between proteins and membranes Nat Commun. 2021 11 09; 12(1):6466. . View in PubMed

Annexin B12 Trimer Formation is Governed by a Network of Protein-Protein and Protein-Lipid Interactions Sci Rep. 2020 03 24; 10(1):5301. . View in PubMed

Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils Biophys J. 2020 11 17; 119(10):2019-2028. . View in PubMed

An Amphipathic Alpha-Helix Domain from Poliovirus 2C Protein Tubulate Lipid Vesicles Viruses. 2020 12 18; 12(12). . View in PubMed

Discovery of Small Molecule Inhibitors of Huntingtin Exon 1 Aggregation by FRET-Based High-Throughput Screening in Living Cells ACS Chem Neurosci. 2020 08 05; 11(15):2286-2295. . View in PubMed

Lipid-modulation of membrane insertion and refolding of the apoptotic inhibitor Bcl-xL Biochim Biophys Acta Proteins Proteom. 2019 Jul - Aug; 1867(7-8):691-700. . View in PubMed

The Mitochondrial Peptide Humanin Targets but Does Not Denature Amyloid Oligomers in Type II Diabetes J Am Chem Soc. 2019 09 11; 141(36):14168-14179. . View in PubMed

Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation MechanismsStructure. 2019 10 01; 27(10):1570-1580. e4. . View in PubMed

E46K-like a-synuclein mutants increase lipid interactions and disrupt membrane selectivity J Biol Chem. 2019 06 21; 294(25):9799-9812. . View in PubMed

Membranes as modulators of amyloid protein misfolding and target of toxicity Biochim Biophys Acta Biomembr. 2018 Sep; 1860(9):1863-1875. . View in PubMed

Pericyte degeneration causes white matter dysfunction in the mouse central nervous system Nat Med. 2018 03; 24(3):326-337. . View in PubMed

Heterotetrameric annexin A2/S100A10 (A2t) is essential for oncogenic human papillomavirus trafficking and capsid disassembly, and protects virions from lysosomal degradation Sci Rep. 2018 08 03; 8(1):11642. . View in PubMed

Directed Supramolecular Organization of N-BAR Proteins through Regulation of H0 Membrane Immersion Depth Sci Rep. 2018 11 06; 8(1):16383. . View in PubMed

Identification of distinct conformations associated with monomers and fibril assemblies of mutant huntingtin Hum Mol Genet. 2018 07 01; 27(13):2330-2343. . View in PubMed

The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract J Biol Chem. 2018 12 21; 293(51):19613-19623. . View in PubMed

The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms J Biol Chem. 2018 02 16; 293(7):2597-2605. . View in PubMed

Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR J Magn Reson. 2017 07; 280:127-139. . View in PubMed

The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity Sci Rep. 2017 08 10; 7(1):7802. . View in PubMed

Structural insights into the activation mechanism of dynamin-like EHD ATPases Proc Natl Acad Sci U S A. 2017 05 30; 114(22):5629-5634. . View in PubMed

a-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils J Biol Chem. 2016 Jan 29; 291(5):2310-8. . View in PubMed

Identification and Structural Characterization of the N-terminal Amyloid Core of Orb2 isoform A Sci Rep. 2016 12 06; 6:38265. . View in PubMed

Hydration Dynamics of a Peripheral Membrane Protein J Am Chem Soc. 2016 09 14; 138(36):11526-35. . View in PubMed

Diabetic Risk Factors Promote Islet Amyloid Polypeptide Misfolding by a Common, Membrane-mediated Mechanism Sci Rep. 2016 08 17; 6:31094. . View in PubMed

O-GlcNAc modification blocks the aggregation and toxicity of the protein a-synuclein associated with Parkinson's disease Nat Chem. 2015 Nov; 7(11):913-20. . View in PubMed

Membrane Curvature-sensing and Curvature-inducing Activity of Islet Amyloid Polypeptide and Its Implications for Membrane Disruption J Biol Chem. 2015 Oct 23; 290(43):25782-93. . View in PubMed

Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography J Biol Chem. 2015 Jul 10; 290(28):17451-61. . View in PubMed

Solid-State Nuclear Magnetic Resonance on the Static and Dynamic Domains of Huntingtin Exon-1 Fibrils Biochemistry. 2015 Jun 30; 54(25):3942-9. . View in PubMed

Tubulation by amphiphysin requires concentration-dependent switching from wedging to scaffolding Structure. 2015 May 05; 23(5):873-881. . View in PubMed

Computer Modeling of Spin Labels: NASNOX, PRONOX, and ALLNOX Methods Enzymol. 2015; 563:569-93. . View in PubMed

Structural Characterization of Membrane-Curving Proteins: Site-Directed Spin Labeling, EPR, and Computational Refinement Methods Enzymol. 2015; 564:259-88. . View in PubMed

Nonaggregated a-synuclein influences SNARE-dependent vesicle docking via membrane binding Biochemistry. 2014 Jun 24; 53(24):3889-96. . View in PubMed

Endophilin A1 induces different membrane shapes using a conformational switch that is regulated by phosphorylation Proc Natl Acad Sci U S A. 2014 May 13; 111(19):6982-7. . View in PubMed

Structural insights into membrane interaction and caveolar targeting of dynamin-like EHD2 Structure. 2014 Mar 04; 22(3):409-420. . View in PubMed

Polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy PLoS One. 2014; 9(12):e112262. . View in PubMed

Hydration dynamics as an intrinsic ruler for refining protein structure at lipid membrane interfaces Proc Natl Acad Sci U S A. 2013 Oct 15; 110(42):16838-43. . View in PubMed

a-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles J Biol Chem. 2013 Jun 14; 288(24):17620-30. . View in PubMed

Visual arrestin interaction with clathrin adaptor AP-2 regulates photoreceptor survival in the vertebrate retina Proc Natl Acad Sci U S A. 2013 Jun 04; 110(23):9463-8. . View in PubMed

ß-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes. 2013 Feb; 62(2):327-35.. View in PubMed

Rational design of potent domain antibody inhibitors of amyloid fibril assembly Proc Natl Acad Sci U S A. 2012 Dec 04; 109(49):19965-70. . View in PubMed

Idealized models of protofilaments of human islet amyloid polypeptide J Chem Inf Model. 2012 Nov 26; 52(11):2983-91. . View in PubMed

Membrane binding and self-association of the epsin N-terminal homology domain J Mol Biol. 2012 Nov 09; 423(5):800-17. . View in PubMed

Structural features and domain organization of huntingtin fibrils J Biol Chem. 2012 Sep 14; 287(38):31739-46. . View in PubMed

Remodeling of lipid vesicles into cylindrical micelles by a-synuclein in an extended a-helical conformation J Biol Chem. 2012 Aug 24; 287(35):29301-11. . View in PubMed

Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5-/- or Mfge8-/- mouse retina Proc Natl Acad Sci U S A. 2012 May 22; 109(21):8145-8. . View in PubMed

Semisynthetic, site-specific ubiquitin modification of a-synuclein reveals differential effects on aggregation J Am Chem Soc. 2012 Mar 28; 134(12):5468-71. . View in PubMed

Fibril structure of human islet amyloid polypeptide J Biol Chem. 2012 Feb 17; 287(8):5235-41. . View in PubMed

Secondary and tertiary structure of bacteriorhodopsin in the SDS denatured state Biochemistry. 2012 Feb 14; 51(6):1051-60. . View in PubMed

Computer modeling of nitroxide spin labels on proteins Biopolymers. 2012 Jan; 97(1):35-44. . View in PubMed

The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection PLoS One. 2012; 7(8):e43519. . View in PubMed

Membrane curvature sensing by amphipathic helices: a single liposome study using a-synuclein and annexin B12 J Biol Chem. 2011 Dec 09; 286(49):42603-42614. . View in PubMed

Intracellular curvature-generating proteins in cell-to-cell fusion Biochem J. 2011 Dec 01; 440(2):185-93. . View in PubMed

A compact beta model of huntingtin toxicity J Biol Chem. 2011 Mar 11; 286(10):8188-8196. . View in PubMed

Beta-cell selective K(ATP)-channel activation protects beta-cells and human islets from human islet amyloid polypeptide induced toxicity Regul Pept. 2010 Dec 10; 165(2-3):158-62. . View in PubMed

Quantifying Membrane Curvature Generation of Drosophila Amphiphysin N-BAR Domains J Phys Chem Lett. 2010 Nov 16; 1(23):3401-3406. . View in PubMed

Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins J Biol Chem. 2010 Oct 15; 285(42):32486-93. . View in PubMed

The effect of curcumin on human islet amyloid polypeptide misfolding and toxicity Amyloid. 2010 Sep; 17(3-4):118-28. . View in PubMed

Monitoring apoptosis and neuronal degeneration by real-time detection of phosphatidylserine externalization using a polarity-sensitive indicator of viability and apoptosis Nat Protoc. 2010 Aug; 5(8):1396-405. . View in PubMed

Multiple modes of endophilin-mediated conversion of lipid vesicles into coated tubes: implications for synaptic endocytosis J Biol Chem. 2010 Jul 23; 285(30):23351-8. . View in PubMed

A combinatorial NMR and EPR approach for evaluating the structural ensemble of partially folded proteins J Am Chem Soc. 2010 Jun 30; 132(25):8657-68. . View in PubMed

Roles of amphipathic helices and the bin/amphiphysin/rvs (BAR) domain of endophilin in membrane curvature generation J Biol Chem. 2010 Jun 25; 285(26):20164-70. . View in PubMed

Stacked sets of parallel, in-register beta-strands of beta2-microglobulin in amyloid fibrils revealed by site-directed spin labeling and chemical labeling J Biol Chem. 2010 May 28; 285(22):17137-47. . View in PubMed

Soluble and mature amyloid fibrils in drusen deposits Invest Ophthalmol Vis Sci. 2010 Mar; 51(3):1304-10. . View in PubMed

Fibrillar oligomers nucleate the oligomerization of monomeric amyloid beta but do not seed fibril formation J Biol Chem. 2010 Feb 26; 285(9):6071-9. . View in PubMed

Engineering a polarity-sensitive biosensor for time-lapse imaging of apoptotic processes and degeneration Nat Methods. 2010 Jan; 7(1):67-73. . View in PubMed

Annexin A5 directly interacts with amyloidogenic proteins and reduces their toxicity Biochemistry. 2009 Nov 10; 48(44):10568-76. . View in PubMed

Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement Proc Natl Acad Sci U S A. 2008 Dec 16; 105(50):19666-71. . View in PubMed

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin Mol Neurodegener. 2008 Oct 21; 3:16. . View in PubMed

Fibrils with parallel in-register structure constitute a major class of amyloid fibrils: molecular insights from electron paramagnetic resonance spectroscopy Q Rev Biophys. 2008 Aug-Nov; 41(3-4):265-97. . View in PubMed

Structure of alpha-helical membrane-bound human islet amyloid polypeptide and its implications for membrane-mediated misfolding J Biol Chem. 2008 Jun 20; 283(25):17205-10. . View in PubMed

Investigation of alpha-synuclein fibril structure by site-directed spin labeling J Biol Chem. 2007 Aug 24; 282(34):24970-9. . View in PubMed

Membrane interaction of islet amyloid polypeptide Biochim Biophys Acta. 2007 Aug; 1768(8):2002-9. . View in PubMed

Structure and analysis of FCHo2 F-BAR domain: a dimerizing and membrane recruitment module that effects membrane curvature Structure. 2007 Jul; 15(7):839-52. . View in PubMed

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. . View in PubMed

Side chain-dependent stacking modulates tau filament structure J Biol Chem. 2006 Dec 08; 281(49):37820-7. . View in PubMed

Inhibition of human IAPP fibril formation does not prevent beta-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP Am J Physiol Endocrinol Metab. 2006 Dec; 291(6):E1317-24. . View in PubMed

Mechanism of endophilin N-BAR domain-mediated membrane curvature EMBO J. 2006 Jun 21; 25(12):2898-910. . View in PubMed

Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers J Clin Invest. 2006 Feb; 116(2):378-85. . View in PubMed

A novel calcium-independent peripheral membrane-bound form of annexin B12 Biochemistry. 2006 Jan 24; 45(3):934-42. . View in PubMed

Spin labeling analysis of amyloids and other protein aggregates Methods Enzymol. 2006; 413:122-39. . View in PubMed

Calcium- and membrane-induced changes in the structure and dynamics of three helical hairpins in annexin B12 Biochemistry. 2005 Dec 20; 44(50):16435-44. . View in PubMed

Light causes phosphorylation of nonactivated visual pigments in intact mouse rod photoreceptor cells J Biol Chem. 2005 Dec 16; 280(50):41184-91. . View in PubMed

A helical hairpin region of soluble annexin B12 refolds and forms a continuous transmembrane helix at mildly acidic pH J Biol Chem. 2005 Sep 16; 280(37):32398-404. . View in PubMed

Lipid membranes modulate the structure of islet amyloid polypeptide Biochemistry. 2005 Sep 13; 44(36):12113-9. . View in PubMed

Evidence for a triplex DNA conformation at the bcl-2 major breakpoint region of the t(14;18) translocation J Biol Chem. 2005 Jun 17; 280(24):22749-60. . View in PubMed

The conserved core domains of annexins A1, A2, A5, and B12 can be divided into two groups with different Ca2+-dependent membrane-binding properties Biochemistry. 2005 Mar 01; 44(8):2833-44. . View in PubMed

Alpha-synuclein structures from fluorescence energy-transfer kinetics: implications for the role of the protein in Parkinson's disease Proc Natl Acad Sci U S A. 2004 Nov 23; 101(47):16466-71. . View in PubMed

Identifying structural features of fibrillar islet amyloid polypeptide using site-directed spin labeling J Biol Chem. 2004 Nov 12; 279(46):48420-5. . View in PubMed

Stability and strand asymmetry in the non-B DNA structure at the bcl-2 major breakpoint region J Biol Chem. 2004 Oct 29; 279(44):46213-25. . View in PubMed

Structure and dynamics of a helical hairpin that mediates calcium-dependent membrane binding of annexin B12 J Biol Chem. 2004 Jul 30; 279(31):32492-8. . View in PubMed

Template-assisted filament growth by parallel stacking of tau Proc Natl Acad Sci U S A. 2004 Jul 13; 101(28):10278-83. . View in PubMed

Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling Proc Natl Acad Sci U S A. 2004 Jun 01; 101(22):8331-6. . View in PubMed

Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling J Biol Chem. 2003 Sep 26; 278(39):37530-5. . View in PubMed

Global structural changes in annexin 12The roles of phospholipid, Ca2+, and pH. J Biol Chem. 2003 Aug 08; 278(32):30227-34. . View in PubMed

The Habc domain and the SNARE core complex are connected by a highly flexible linker Biochemistry. 2003 Apr 15; 42(14):4009-14. . View in PubMed

Rapid and selective binding to the synaptic SNARE complex suggests a modulatory role of complexins in neuroexocytosis J Biol Chem. 2002 Mar 08; 277(10):7838-48. . View in PubMed

Structure and dynamics of a helical hairpin and loop region in annexin 12: a site-directed spin labeling study Biochemistry. 2002 Feb 05; 41(5):1464-73. . View in PubMed

Calcium-dependent binding of annexin 12 to phospholipid bilayers: stoichiometry and implications Biochemistry. 2001 Jun 19; 40(24):7054-60. . View in PubMed

Homo- and heterooligomeric SNARE complexes studied by site-directed spin labeling J Biol Chem. 2001 Apr 20; 276(16):13169-77. . View in PubMed

Crystal structures of spin labeled T4 lysozyme mutants: implications for the interpretation of EPR spectra in terms of structure Biochemistry. 2000 Jul 25; 39(29):8396-405. . View in PubMed

Annexins V and XII insert into bilayers at mildly acidic pH and form ion channels Biochemistry. 2000 Mar 21; 39(11):3015-22. . View in PubMed

Structural features of the C-terminal domain of bovine rhodopsin: a site-directed spin-labeling study Biochemistry. 1999 Jun 22; 38(25):7918-24. . View in PubMed

A transmembrane form of annexin XII detected by site-directed spin labeling Proc Natl Acad Sci U S A. 1998 Nov 24; 95(24):14060-5. . View in PubMed

Recent advances in site-directed spin labeling of proteins Curr Opin Struct Biol. 1998 Oct; 8(5):649-56. . View in PubMed

Membrane-mediated assembly of annexins studied by site-directed spin labeling J Biol Chem. 1998 Aug 28; 273(35):22453-7. . View in PubMed

Structure and function in rhodopsin: topology of the C-terminal polypeptide chain in relation to the cytoplasmic loops Proc Natl Acad Sci U S A. 1997 Dec 23; 94(26):14267-72. . View in PubMed

Electrostatic control of GTP and GDP binding in the oncoprotein p21ras Structure. 1996 Apr 15; 4(4):475-89. . View in PubMed

Electron tunneling in proteins: role of the intervening medium Journal of Biological Inorganic Chemistry. 1996; 1(3):221. . View in PubMed

Electron tunneling in proteins: coupling through a beta strand Science. 1995 Jun 23; 268(5218):1733-5. . View in PubMed

Electron transfer in ruthenium-modified proteins J Bioenerg Biomembr. 1995 Jun; 27(3):295-302. . View in PubMed

Why have mutagenesis studies not located the general base in ras p21 Nat Struct Biol. 1994 Jul; 1(7):476-84. . View in PubMed

Protein control of iron-sulfur cluster redox potentials J Biol Chem. 1992 Dec 25; 267(36):25625-7. . View in PubMed

On the mechanism of guanosine triphosphate hydrolysis in ras p21 proteins Biochemistry. 1992 Sep 22; 31(37):8691-6. . View in PubMed

Effect of the Asn52----Ile mutation on the redox potential of yeast cytochrome cTheory and experiment. J Mol Biol. 1992 Apr 05; 224(3):589-600. . View in PubMed

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.
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