title: Calcium-induced conformational changes of Thrombospondin-1 signature domain: implications for vascular disease.
abstract: BACKGROUND
  Thrombospondin1 (TSP1) participates in numerous signaling pathways critical for vascular physiology and disease. The conserved signature domain of thrombospondin 1 (TSP1-Sig1) comprises three epidermal growth factor (EGF), 13 calcium-binding type 3 thrombospondin (T3) repeats, and one lectin-like module arranged in a stalk-wire-globe topology. TSP1 is known to be present in both calcium-replete (Holo-) and calcium-depleted (Apo-) state, each with distinct downstream signaling effects.
  
  
  OBJECTIVE
  To prepare a homology model of TSP1-Sig1 and investigate the effect of calcium on its dynamic structure and interactions.
  
  
  METHODS
  A homology model of Holo-TSP1-Sig1 was prepared with TSP2 as template in Swissmodel workspace. The Apo-form of the model was obtained by omitting the bound calcium ions from the homology model. Molecular dynamics (MD) simulation studies (100 ns) were performed on the Holo- and Apo- forms of TSP1 using Gromacs4.6.5.
  
  
  CONCLUSIONS
  After simulation, Holo-TSP1-Sig1 showed significant reorientation at the interface of the EGF1-2 and EGF2-3 modules. The T3 wire is predicted to show the maximum mobility and deviation from the initial model. In Apo-TSP1-Sig1 model, the T3 repeats unfolded and formed coils with predicted increase in flexibility. Apo-TSP1-Sig1model also predicted the exposure of the binding sites for neutrophil elastase, integrin and fibroblast growth factor 2. We present a structural model and hypothesis for the role of TSP1-Sig1 interactions in the development of vascular disorders.
  
  
  CONCLUSIONS
  The simulated model of the fully calcium-loaded and calcium-depleted TSP1-Sig1 may enable the development of its interactions as a novel therapeutic target for the treatment of vascular diseases.
authors.affiliation: a Computational and Structural Biology Laboratory, Division of Biotechnology , Netaji Subhas Institute of Technology , Dwarka , New Delhi , India.|b Department of Biotechnology , IMS Engineering College , Ghaziabad , Uttar Pradesh , India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: c Department of Life Sciences, School of Natural Sciences , Shiv Nadar University , Uttar Pradesh , India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: c Department of Life Sciences, School of Natural Sciences , Shiv Nadar University , Uttar Pradesh , India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Singh
authors.affiliation: a Computational and Structural Biology Laboratory, Division of Biotechnology , Netaji Subhas Institute of Technology , Dwarka , New Delhi , India.
authors.forename: Sonika
authors.initials: S
authors.lastname: Bhatnagar
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation / Q000187:drug effects; D000072417:Protein Domains / Q000235:genetics; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000378:metabolism; D019699:Thrombospondins / Q000737:chemistry / Q000235:genetics*; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D019700:Thrombospondin 1; D019699:Thrombospondins; C101863:thrombospondin 3; C000611726:thrombospondin-1, human; D004815:Epidermal Growth Factor; D002118:Calcium
keywords: Thrombospondin-1 signature domain; calcium ions; homology modeling; molecular dynamics simulation; vascular disease