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Calcium-induced conformational changes of Thrombospondin-1 signature domain: implications for vascular disease

Akanksha Gupta1,2, Rahul Agarwal3, Ashutosh Singh3

  • 1a Computational and Structural Biology Laboratory, Division of Biotechnology , Netaji Subhas Institute of Technology , Dwarka , New Delhi , India.

Journal of Receptor and Signal Transduction Research
|August 4, 2016
PubMed

Insights

Calcium

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Dynamics

Background:

  • Thrombospondin 1 (TSP1) is crucial in vascular signaling and disease.
  • Its signature domain (TSP1-Sig1) has EGF, calcium-binding T3 repeats, and a lectin-like module.
  • TSP1 exists in calcium-replete (Holo-) and calcium-depleted (Apo-) states with different signaling effects.

Purpose of the Study:

  • To create a homology model of TSP1-Sig1.
  • To investigate calcium's effect on TSP1-Sig1's dynamic structure and interactions.

Main Methods:

  • Homology modeling of Holo-TSP1-Sig1 using TSP2 as a template.
  • Generating the Apo-form by removing calcium ions.
  • Conducting 100 ns molecular dynamics (MD) simulations on both forms using Gromacs.

Main Results:

  • Holo-TSP1-Sig1 showed reorientation between EGF modules.
  • The T3 repeats exhibited high mobility.
  • Apo-TSP1-Sig1 displayed unfolded T3 repeats, increased flexibility, and exposed binding sites for neutrophil elastase, integrin, and FGF2.

Conclusions:

  • The study presents a structural model and hypothesis for TSP1-Sig1's role in vascular disorders.
  • Simulated models of calcium-loaded and depleted TSP1-Sig1 can guide therapeutic strategies.
  • Targeting TSP1-Sig1 interactions offers potential for novel vascular disease treatments.
Abstract

Keywords:
Thrombospondin-1 signature domaincalcium ionshomology modelingmolecular dynamics simulationvascular disease

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