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Nicholson, Linda K
Cornell Faculty Member
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Affiliations
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- David R. Atkinson Center for a Sustainable Future (ACSF) Faculty Fellow
Research
research overview
- The overall objective of my research program is to gain a fundamental understanding of protein function and regulation from a perspective that includes both atomic resolution structure and dynamic fluctuations within this structure. I have exploited systems in which the regulation and/or function of a specific protein is amenable to study using biophysical methods, principally NMR spectroscopy. In recent years my work has focused on proteins that are regulated by phosphorylation (the cytoplasmic tail of the amyloid precursor protein and Ezrin), as well as proteins that facilitate key aspects of infection by pathogenic bacteria (OspA and AvrPto). The common element in these research endeavors is the establishment of relationships between atomic level structural and dynamic features of a specific protein and its function in the cell, with emphasis on proteins with an established role in disease. It is my opinion that one of the most exciting and important challenges in science today is to understand the relationships between protein dynamics and cellular dynamics. For cases in which a specific protein is identified as a key regulatory element of a given biological process, and for which a cellular output of the process can be measured, it should be possible to extract relationships between protein kinetics (and the actual intra- and intermolecular dynamics that facilitate activity) and the kinetics of the measured cellular output. Currently, my lab is investigating two such biological systems that are allowing us to begin to establish direct links between dynamics at the sub-molecular and cellular levels. In one system we are investigating the influence of the enzyme Pin1 on the proteolytic processing fate of the amyloid precursor protein, while in the second system we are examining links between the folding of effector protein AvrPto and its efficiency of secretion and translocation by the T3SS.
principal investigator on
- CONFORMATIONAL DYNAMICS IN PIN 1 REGULATION OF APP PROCESSING AND ABETA PRODUCTION awarded by NATL INST OF HEALTH DHHS 2007 - 2013
- ESTABLISHING THE THERMODYNAMIC AND KINETIC THRESHOLDS FOR BATERIAL PROTEIN SECRETION VIA TYPE 3 SECRETION SYSTEM awarded by NATL SCIENCE FOUNDATION 2007 - 2013
- ISOMER-SPECIFIC INTERACTIONS OF X-PRO MOTIFS: INVESTIGATING FUNDAMENTAL MECHANISMS OF SIGNALING BY PROLINE-RICH SEQUENCES awarded by NATL SCIENCE FOUNDATION 2012 - 2015
co-principal investigator on
- TRAINING IN MOLECULAR PHYSICS OF BIOLOGICAL SYSTEMS awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2012 - 2017
keywords
- Alzheimer's Disease
- Cancer
- Mechanisms of Pathogen Infection
- Protein Dynamics
- Protein NMR Spectroscopy
- Structural Biology
submitted impact statement
Publications
individual publications
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academic article
- The twist in Crk signaling revealed. Nature Chemical Biology. 7:5-6. 2011
- The single kinin receptor signals to separate aand independent physiological pathways in Malpighian tubules of the yellow fever mosquito. Am J Physiol Regul Integr Comp Physiol. 299. 2010
- A novel fibronectin type III module binding motif identified on C-terminus of Leptospira immunoglobulin-like protein, LigB. Biochemical and Biophysical Research Communications. 223:491-467. 2009
- Elucidation of a pH-dependent folding switch in the Pseudomonas syringae effector protein AvrPto. Proceedings of the National Academy of Sciences of the United States of America. 106:8543-8548. 2009
- Fibronectin Binds to and Induces Conformational Change in a Disordered Region of Leptospiral Immunoglobulin-like Protein B. Journal of Biological Chemistry. 284:23547-23557. 2009
- Repeated Domains of Leptospira Immunoglobulin-like Proteins Interact with Elastin and Tropoelastin. Journal of Biological Chemistry. 284:19380-19391. 2009
- Folding kinetics and thermodynamics of Pseudomonas syringae effector protein AvrPto provide insight into transolcation via the Type III secretion system. Protein Science. 17:1109-1119. 2008
- Prolyl cis-trans isomerization as a molecular timer. Nature Chemical Biology. 3:619-629. 2007
- Prolyl cis/trans Isomerization as a Molecular Timer in Crk Signaling. Molecular Cell. 25:483-485. 2007
- The N-terminal region of Pseudomonas type III effector AvrPtoB elicits Pto-dependent immunity and has two distinct virulence determinants. The Plant Journal. 52:595-614. 2007
- Thermodynamic Dissection of the Ezrin FERM/CERMAD Interface. Biochemistry. 46:12174-12189. 2007
- Letter to the Editor: Backbone Resonance Assignments of Ezrin C ERMAD in a Non-covalent Complex with Ezrin N FERM. Journal of Biomolecular NMR. 36:63. 2006
- The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid- production. Nature. 440:528-534. 2006
- The solution structure of type III effector protein AvrPto reveals conformational and dynamic features important for plant pathogenesis. Structure. 12:1257-1268. 2004
- 1H, 15N and 13C chemical shift assignments of the structured core of the Pseudomonas effector protein AvrPto. Journal of Biomolecular NMR. 23:247-248. 2002
- Backbone Dynamics and Thermodynamics of Borrelia Outer Surface Protein A. Journal of Molecular Biology. 324:991-1002. 2002
- Factors Determining the Reliable Description of Global Tumbling Parameters in Solution NMR. Journal of Biomolecular NMR. 24:215-229. 2002
- 1H, 15N and 13C chemical shift assignments of a monomeric N-terminal deletion mutant of the Rous sarcoma virus protease. Journal of Biomolecular NMR. 19:279-280. 2001
- An Improved Method for Distinguishing Between Anisotropic Tumbling and Chemical Exchange in Analysis of 15N Relaxation Parameters. Journal of Biomolecular NMR. 20:149-165. 2001
- An increase in side chain entropy facilitates effector binding: NMR characterization of the side chain methyl group dynamics in cdc42Hs. Biochemistry. 40:4590-4600. 2001
- Importance of the N-terminus of Rous sarcoma virus protease for structure and enzymatic function. Journal of Virology. 75:4761-4770. 2001
- Phosphorylation-Induced Structural Changes in the Amyloid Precursor Protein Cytoplasmic Tail Detected by NMR. Journal of Molecular Biology. 307:871-884. 2001
- Solution Structure of ThiS and Implications for the Evolutionary Roots of Ubiquitin. Nature Structural Biology. 8:47-51. 2001
- The Role of Backbone Motions in Ligand Binding to the c-Src SH3 Domain. Journal of Molecular Biology. 313:873-887. 2001
- Ligand-induced strain in the c-Src SH3 domain detected by NMR. Journal of Molecular Biology. 304:497-505. 2000
- Protein dynamics measurements by TROSY-based NMR experiments. Journal of Magnetic Resonance. 143:423-426. 2000
- Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors. Biochemistry. 39:2714-2725. 2000
- Backbone dynamics of inactive, active, and effector-bound Cdc42Hs from measurements of N-15 relaxation parameters at multiple field strengths. Biochemistry. 38:12547-12557. 1999
- Gramicidin Channel Controversy – Revisited. Nature Structural Biology. 6:610-611. 1999
- Heteronuclear NMR studies of the combined SH3-SH2 domains of pp60c-src. The effects of phosphopeptide binding. Biochemistry. 36:14561-14571. 1997
- Three Dimensional Solution Structure of the HIV-1 Protease/DMP323 Complex Determined by NMR Spectroscopy. Protein Science. 5:495-506. 1996
- Flexibility and Function in the HIV-1 Protease. Nature Structural Biology. 2:274-280. 1995
- A Structural Analysis of Highly Oriented Poly(p=phenylene-terephthalamide) by Solid State NMR. Solid State NMR. 3:209-218. 1994
- NMR Evidence for the Displacement of a Conserved Interior Water Molecule by a Non-peptide Cyclic Urea Based HIV Protease Inhibitor. Journal of the American Chemical Society. 116:1581-1582. 1994
- NMR and X-Ray Evidence that the HIV Protease Catalytic Aspartyl Groups Have an Essential Role in the Complex Formed by the Protease and a Non-Peptide Cyclic Urea-Based Inhibitor. Journal of the American Chemical Society. 116:10791-10792. 1994
- Secondary Structure and Signal Assignments of HIV-1 Protease Complexed to a Novel, Structure Based Inhibitor. European Journal of Biochemistry. 217:707-712. 1994
- The Measurement of Heteronuclear Transverse Relaxation-Times in AX(3) Spin Systems Via Polarization Transfer Techniques. Journal of Magnetic Resonance. Series A 111:231-232. 1994
- A Method for Studying the Structure of Uniaxially Aligned Biopolymers Using Solid State 15N NMR: Application to Bombyx Mori Silk Fibroin Fibers. Biopolymers. 33:847-861. 1993
- Structural Analysis of Uniaxially-Aligned Polymers Using Solid-State N-15 NMR. Macromolecules. 26:6660-6663. 1993
- Dynamics of Methyl Groups in Proteins as Studied by Proton Detected 13C NMR Spectroscopy. Application to the Leucine Residues of Staphylococcal Nuclease. Biochemistry. 31:5253-5263. 1992
- On the Measurement of Heteronuclear Transverse Relaxation Times in AX3 Spin Systems Via Polarization Transfer Techniques. Journal of Magnetic Resonance. 100:538-558. 1992
- Pulse Sequences for the Removal of the Effects of Cross Correlation between Dipolar and Chemical-Shift Anisotropy Relaxation Mechanisms on the Measurement of Heteronuclear T1 and T2 Values in Proteins. Journal of Magnetic Resonance. 97:359-375. 1992
- A Solid-State NMR-Derived Model for Dynamics in the Polypeptide Backbone of the Gramicidin-A Channel. Journal of Molecular Biology. 218:621-637. 1991
- Membrane Ion Channel Structure by Computational and NMR Spectroscopy. Biophysical Journal. 60:974-978. 1991
- The Experimental Determination of Torsion Angles in the Polypeptide Backbone of the Gramicidin-A Channel by Solid-State NMR. Journal of Molecular Biology. 218:607-619. 1991
- Experimental Observation of the Peptide Librational Motions in the Gramicidin Cation Channel. Journal of the American Chemical Society. 111:400-401. 1989
- N-H Bond Length Determinations and Implications for the Gramicidin Channel Conformation and Dynamics from 15N-1H Dipolar Interactions. Journal of the American Chemical Society. 111:1910-1912. 1989
- The Gramicidin Channel: An Experimental Determination of the Right-Handed Helix Sense and Verification of ß-Type Hydrogen Bonding. Biochemistry. 28:9379-9385. 1989
- Solid-State 15N NMR Evidence that Gramicidin-A can Adopt Two Different Conformations in Dimyristoylphosphatidylcholine Model Membrane Preparations. Biochimica et Biophysica Acta. 943:535-540. 1988
- Solid-State 15N NMR of Oriented Lipid Bilayer-Bound Gramicidin-A. Biochemistry. 26:6621-6626. 1987
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booksection
- NMR Characterization of Silk Proteins. Vol. 544. 1994
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chapter
- Flexibility and Function in the HIV-1 Protease. NMR in Drug Design. 1996
- Protein Dynamics as Studied by Solution NMR Techniques. NMR Spectroscopy and its Application to Biological Research. 1996
- Heteronuclear NMR Studies of the Molecular Dynamics of Staphylococcal Nuclease. Topics in Molecular and Structural Biology Series: NMR of Proteins. 1993
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conference paper
- Mechanisms of Regulation in the Regulatory Apparatus of pp60 c-Src. Structure, Motion, Interaction and Expression of Biological Macromolecules. Proceedings of the Tenth Conversation, State University of New York, Albany, NY 1997. 1998
featured in archived article
speaker at Cornell event
Teaching
Service
service to the profession
- AMERICAN CHEMICAL SOCIETY Member 2000 -
- Protein Society Member 2000 -
- Biophysical Society Member 1996 -
- American Association for the Advancement of Science Member 1986 -
- SIGMA XI Member 1982 -
- The Raven Society Member 1982 -
- Omicron Delta Kappa Member 1981 -
- Pi Tau Sigma Member 1979 -
- Tau Beta Phi Member 1979 -
- UNYCOR Structural Biology Group
- Biomolecular Interactions and Methods GRC Chair - 2012
- Biomolecular Interactions and Methods GRC Chair-Elect - 2010
- National Advisory Board, NMRFAM (National Magnetic Resonance Facility at Madison), NIH Research Resource Program Chairperson 2006
- National Advisory Board, NMRFAM (National Magnetic Resonance Facility at Madison), NIH Research Resource Program Member 2002 - 2006
- PhD Defense of Arianna Roth, University of Toronto External Examiner - 2004
- Academic Screening Committee, National Physical Sciences Consortium Committee Member - 1997
- Association for Women in Science Member 1988 - 1994
reviewer or editor for
Background
education and training
- Ph.D. in Molecular Biophysics, Florida State University 1990
- M.S. in Mechanical Engineering, University of Virginia 1985
- B.S. in Mechanical Engineering, University of Virginia 1982
awards and honors
- Selected by Dean's Scholar Ian Odell as "Most Admired Faculty Member", 2004
- Shannon Award, 1999
- Recognized as Faculty Mentor by Merrell Scholar Katherine Henzler, 1998
- Kasha Lecturer, 1995
- Fisher Award Finalist, 1990
- College Teaching Fellowship (1985-1986), 1985
- Graduate Fellowship (1983-1984), 1983
- Jettie Hill Memorial Award, 1982
- Ingersoll Rand Scholarship Award, 1982
Other
research keyword
- Alzheimer's Disease
- Cancer
- Mechanisms of Pathogen Infection
- Protein Dynamics
- Protein NMR Spectroscopy
- Structural Biology