Article thumbnail

Force-Induced Unfolding Simulations of the Human Notch1 Negative Regulatory Region: Possible Roles of the Heterodimerization Domain in Mechanosensing

By Jianhan Chen and Anna Zolkiewska

Abstract

Notch receptors are core components of the Notch signaling pathway and play a central role in cell fate decisions during development as well as tissue homeostasis. Upon ligand binding, Notch is sequentially cleaved at the S2 site by an ADAM protease and at the S3 site by the γ-secretase complex. Recent X-ray structures of the negative regulatory region (NRR) of the Notch receptor reveal an auto-inhibited fold where three protective Lin12/Notch repeats (LNR) of the NRR shield the S2 cleavage site housed in the heterodimerization (HD) domain. One of the models explaining how ligand binding drives the NRR conformation from a protease-resistant state to a protease-sensitive one invokes a mechanical force exerted on the NRR upon ligand endocytosis. Here, we combined physics-based atomistic simulations and topology-based coarse-grained modeling to investigate the intrinsic and force-induced folding and unfolding mechanisms of the human Notch1 NRR. The simulations support that external force applied to the termini of the NRR disengages the LNR modules from the heterodimerization (HD) domain in a well-defined, largely sequential manner. Importantly, the mechanical force can further drive local unfolding of the HD domain in a functionally relevant fashion that would provide full proteolytic access to the S2 site prior to heterodimer disassociation. We further analyzed local structural features, intrinsic folding free energy surfaces, and correlated motions of the HD domain. The results are consistent with a model in which the HD domain possesses inherent mechanosensing characteristics that could be utilized during Notch activation. This potential role of the HD domain in ligand-dependent Notch activation may have implications for understanding normal and aberrant Notch signaling

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3145759
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2000). A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.
  2. (2000). A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.
  3. (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
  4. (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.
  5. (1998). All-atom empirical potential for molecular modeling and dynamics studies of proteins.
  6. (2009). Atomistic details of the disordered states of KID and pKID. implications in coupled binding and folding.
  7. (2006). Balancing solvation and intramolecular interactions: Toward a consistent generalized born force field.
  8. (1983). Charmm - a Program for Macromolecular Energy, Minimization, and Dynamics Calculations.
  9. (2009). CHARMM: The Biomolecular Simulation Program.
  10. (1998). Crystal structure of the catalytic domain of human tumor necrosis factoralpha-converting enzyme.
  11. (2005). Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila.
  12. (2004). Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch.
  13. (2007). DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur.
  14. (2011). Evidence for Increased Exposure of the Notch1 Metalloprotease Cleavage Site upon Conversion to an Activated Conformation.
  15. (2006). Exploring atomistic details of pHdependent peptide folding.
  16. (2004). Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations.
  17. (2007). Folding intermediate in the villin headpiece domain arises from disruption of a N-terminal hydrogen-bonded network.
  18. (2003). Force field influence on the observation of pi-helical protein structures in molecular dynamics simulations.
  19. (2003). Generalized born model with a simple smoothing function.
  20. (2006). High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia.
  21. (2000). Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling.
  22. (1999). Implicit solvent models.
  23. (2004). Improved treatment of the protein backbone in empirical force fields.
  24. (2009). Insights from Coarse-Grained Go Models for Protein Folding and Dynamics.
  25. (2004). Integrating folding kinetics and protein function: Biphasic kinetics and dual binding specificity in a WW domain.
  26. (2009). Intrinsically disordered p53 extreme C-terminus binds to S100B(betabeta) through ‘‘fly-casting’’.
  27. (2006). Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.
  28. (1996). Ligand binding: Molecular mechanics calculation of the streptavidin biotin rupture force.
  29. (2000). Ligand endocytosis drives receptor dissociation and activation in the Notch pathway.
  30. (2001). Ligandinduced signaling in the absence of furin processing of Notch1.
  31. (2007). Linking folding with aggregation in Alzheimer’s beta-amyloid peptides.
  32. (2006). Mechanical resistance of proteins explained using simple molecular models.
  33. (2010). Mechanistic insights into Notch receptor signaling from structural and biochemical studies.
  34. (2008). Mechanoenzymatics of titin kinase.
  35. (2009). Metalloprotease ADAM10 is required for Notch1 site 2 cleavage.
  36. (2004). MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology.
  37. (2010). Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy.
  38. (2008). More complicated than it looks: assembly of Notch pathway transcription complexes.
  39. (1999). Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants.
  40. (2008). Notch signaling in leukemia.
  41. (2010). Notch signaling in solid tumors.
  42. (2009). Notch signaling: the core pathway and its posttranslational regulation.
  43. (2010). Notch: the past, the present, and the future.
  44. (1977). Numerical-Integration of Cartesian Equations of Motion of a System with Constraints - MolecularDynamics of N-Alkanes.
  45. (1999). Presenilin is required for activity and nuclear access of Notch in Drosophila.
  46. (2001). Protein folding theory: From lattice to all-atom models.
  47. (2003). Pulling geometry defines the mechanical resistance of a beta-sheet protein.
  48. (2008). Recent advances in implicit solvent based methods for biomolecular simulations.
  49. (2005). Recent successes of the energy landscape theory of protein folding and function.
  50. (1999). Replica-exchange molecular dynamics method for protein folding.
  51. (1997). Requirement for dynamin during Notch signaling in Drosophila neurogenesis.
  52. (1996). Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading.
  53. (2009). Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling.
  54. (2010). Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.
  55. (2007). Structural basis for autoinhibition of Notch.
  56. (2009). Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL.
  57. (2007). Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.
  58. (2008). Subdomain competition, cooperativity, and topological frustration in the folding of CheY.
  59. (2005). Temperature weighted histogram analysis method, replica exchange, and transition paths.
  60. (2008). The ADAM metalloproteinases.
  61. (1995). The calculation of the potential of mean force using computer simulations.
  62. (2009). The canonical Notch signaling pathway: unfolding the activation mechanism.
  63. (2002). The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.
  64. (2008). The molecular logic of Notch signaling - a structural and biochemical perspective.
  65. (1998). The Notch1 receptor is cleaved constitutively by a furin-like convertase.
  66. (2002). The origins of asymmetry in the folding transition states of protein L and protein G.
  67. (2005). The roles of receptor and ligand endocytosis in regulating Notch signaling.
  68. (2003). The structural basis for biphasic kinetics in the folding of the WW domain from a formin-binding protein: Lessons for protein design?
  69. (1992). The Weighted Histogram Analysis Method for Free-Energy Calculations on Biomolecules .1. the Method.
  70. (1997). Theory of protein folding: The energy landscape perspective.
  71. (2000). Unfolding proteins by external forces and temperature: The importance of topology and energetics.
  72. (1996). VMD: Visual molecular dynamics.
  73. (2006). Why is delta endocytosis required for effective activation of notch?