Recognition Dynamics Up to Microseconds Revealed from an RDC-Derived Ubiquitin Ensemble in Solution

Protein dynamics are essential for protein function, and yet it has been challenging to access the underlying atomic motions in solution on nanosecond-to-microsecond time scales. We present a structural ensemble of ubiquitin, refined against residual dipolar couplings (RDCs), comprising solution dynamics up to microseconds. The ensemble covers the complete structural heterogeneity observed in 46 ubiquitin crystal structures, most of which are complexes with other proteins. Conformational selection, rather than induced-fit motion, thus suffices to explain the molecular recognition dynamics of ubiquitin. Marked correlations are seen between the flexibility of the ensemble and contacts formed in ubiquitin complexes. A large part of the solution dynamics is concentrated in one concerted mode, which accounts for most of ubiquitin's molecular recognition heterogeneity and ensures a low entropic complex formation cost.

[1]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[2]  T. Creighton.  Methods in Enzymology , 1968, The Yale Journal of Biology and Medicine.

[3]  G. Lipari.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules , 1982 .

[4]  A. Szabó,et al.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity , 1982 .

[5]  P. Wolynes,et al.  Rate theories and puzzles of hemeprotein kinetics. , 1985, Science.

[6]  L. Kay,et al.  Backbone dynamics of proteins as studied by 15N inverse detected heteronuclear NMR spectroscopy: application to staphylococcal nuclease. , 1989, Biochemistry.

[7]  AC Tose.  Cell , 1993, Cell.

[8]  Arthur G. Palmer,et al.  NMR order parameters and free energy: an analytical approach and its application to cooperative calcium(2+) binding by calbindin D9k , 1993 .

[9]  V. Hu.  The Cell Cycle , 1994, GWUMC Department of Biochemistry Annual Spring Symposia.

[10]  A. Bax,et al.  Rotational diffusion anisotropy of human ubiquitin from 15N NMR relaxation , 1995 .

[11]  Remo Guidieri.  Res , 1995, RES: Anthropology and Aesthetics.

[12]  T. Clackson,et al.  A hot spot of binding energy in a hormone-receptor interface , 1995, Science.

[13]  J H Prestegard,et al.  Nuclear magnetic dipole interactions in field-oriented proteins: information for structure determination in solution. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Arthur G. Palmer,et al.  Monitoring Macromolecular Motions on Microsecond to Millisecond Time Scales by R1ρ−R1 Constant Relaxation Time NMR Spectroscopy , 1996 .

[15]  L. Kay,et al.  Contributions to protein entropy and heat capacity from bond vector motions measured by NMR spin relaxation. , 1997, Journal of molecular biology.

[16]  A. Bax,et al.  Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. , 1997, Science.

[17]  Ad Bax,et al.  Determination of Relative N−HN, N−C‘, Cα−C‘, and Cα−Hα Effective Bond Lengths in a Protein by NMR in a Dilute Liquid Crystalline Phase , 1998 .

[18]  J Meiler,et al.  Model-free approach to the dynamic interpretation of residual dipolar couplings in globular proteins. , 2001, Journal of the American Chemical Society.

[19]  J. Brender,et al.  Functional dynamics in the active site of the ribonuclease binase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Jens Meiler,et al.  Model-free analysis of protein backbone motion from residual dipolar couplings. , 2002, Journal of the American Chemical Society.

[21]  J. R. Tolman.  A novel approach to the retrieval of structural and dynamic information from residual dipolar couplings using several oriented media in biomolecular NMR spectroscopy. , 2002, Journal of the American Chemical Society.

[22]  Dan S. Tawfik,et al.  Antibody Multispecificity Mediated by Conformational Diversity , 2003, Science.

[23]  Joel R Tolman,et al.  De novo determination of bond orientations and order parameters from residual dipolar couplings with high accuracy. , 2003, Journal of the American Chemical Society.

[24]  M. Nilges,et al.  Complementarity of structure ensembles in protein-protein binding. , 2004, Structure.

[25]  M. Gerstein,et al.  Conformational changes associated with protein-protein interactions. , 2004, Current opinion in structural biology.

[26]  Nico Tjandra,et al.  Temperature dependence of protein backbone motion from carbonyl 13C and amide 15N NMR relaxation. , 2005, Journal of magnetic resonance.

[27]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[28]  Jens Meiler,et al.  Side-chain orientation and hydrogen-bonding imprint supra-Tau(c) motion on the protein backbone of ubiquitin. , 2005, Angewandte Chemie.

[29]  Linda Hicke,et al.  Ubiquitin-binding domains , 2005, Nature Reviews Molecular Cell Biology.

[30]  Rafael Brüschweiler,et al.  Identification of slow correlated motions in proteins using residual dipolar and hydrogen-bond scalar couplings. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Griesinger,et al.  Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. DePristo,et al.  Simultaneous determination of protein structure and dynamics , 2005, Nature.

[33]  A. Palmer,et al.  Microsecond timescale backbone conformational dynamics in ubiquitin studied with NMR R1ρ relaxation experiments , 2005, Protein science : a publication of the Protein Society.

[34]  L. Kay,et al.  Intrinsic dynamics of an enzyme underlies catalysis , 2005, Nature.

[35]  Ke Ruan,et al.  Composite alignment media for the measurement of independent sets of NMR residual dipolar couplings. , 2005, Journal of the American Chemical Society.

[36]  M. DePristo,et al.  Relation between native ensembles and experimental structures of proteins. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Jens Meiler,et al.  A Thorough Dynamic Interpretation of Residual Dipolar Couplings in Ubiquitin , 2006, Journal of biomolecular NMR.

[38]  J. Wade Harper,et al.  Structural Complexity in Ubiquitin Recognition , 2006, Cell.

[39]  D. Boehr,et al.  The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis , 2006, Science.

[40]  P. Hamm,et al.  Watching hydrogen-bond dynamics in a β-turn by transient two-dimensional infrared spectroscopy , 2006, Nature.

[41]  Christina Kiel,et al.  The ubiquitin domain superfold: structure-based sequence alignments and characterization of binding epitopes. , 2006, Journal of molecular biology.

[42]  A. G. Murachelli,et al.  Crystal Structure of the Ubiquitin Binding Domains of Rabex-5 Reveals Two Modes of Interaction with Ubiquitin , 2006, Cell.

[43]  P. Brzovic,et al.  Ubiquitin Transfer from the E2 Perspective: Why is UbcH5 So Promiscuous? , 2006, Cell cycle.

[44]  G. Bouvignies,et al.  Simultaneous determination of protein backbone structure and dynamics from residual dipolar couplings. , 2006, Journal of the American Chemical Society.

[45]  Lewis E. Kay,et al.  New Tools Provide New Insights in NMR Studies of Protein Dynamics , 2006, Science.

[46]  G. Clore,et al.  Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR , 2007, Nature.

[47]  H. Dyson,et al.  Mechanism of coupled folding and binding of an intrinsically disordered protein , 2007, Nature.

[48]  G. Bouvignies,et al.  Exploring multiple timescale motions in protein GB3 using accelerated molecular dynamics and NMR spectroscopy. , 2007, Journal of the American Chemical Society.

[49]  X. Salvatella,et al.  The MUMO (minimal under-restraining minimal over-restraining) method for the determination of native state ensembles of proteins , 2007, Journal of biomolecular NMR.

[50]  A. Wand,et al.  Conformational entropy in molecular recognition by proteins , 2007, Nature.

[51]  M. Karplus,et al.  A hierarchy of timescales in protein dynamics is linked to enzyme catalysis , 2007, Nature.

[52]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.