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Journal of Computer-Aided Molecular Design

, Volume 30, Issue 2, pp 153–164 | Cite as

A β-solenoid model of the Pmel17 repeat domain: insights to the formation of functional amyloid fibrils

  • Nikolaos N. Louros
  • Fotis A. Baltoumas
  • Stavros J. Hamodrakas
  • Vassiliki A. IconomidouEmail author
Article

Abstract

Pmel17 is a multidomain protein involved in biosynthesis of melanin. This process is facilitated by the formation of Pmel17 amyloid fibrils that serve as a scaffold, important for pigment deposition in melanosomes. A specific luminal domain of human Pmel17, containing 10 tandem imperfect repeats, designated as repeat domain (RPT), forms amyloid fibrils in a pH-controlled mechanism in vitro and has been proposed to be essential for the formation of the fibrillar matrix. Currently, no three-dimensional structure has been resolved for the RPT domain of Pmel17. Here, we examine the structure of the RPT domain by performing sequence threading. The resulting model was subjected to energy minimization and validated through extensive molecular dynamics simulations. Structural analysis indicated that the RPT model exhibits several distinct properties of β-solenoid structures, which have been proposed to be polymerizing components of amyloid fibrils. The derived model is stabilized by an extensive network of hydrogen bonds generated by stacking of highly conserved polar residues of the RPT domain. Furthermore, the key role of invariant glutamate residues is proposed, supporting a pH-dependent mechanism for RPT domain assembly. Conclusively, our work attempts to provide structural insights into the RPT domain structure and to elucidate its contribution to Pmel17 amyloid fibril formation.

Keywords

Molecular dynamics Homology modelling β-Helix Functional amyloid Amyloid fibrils 

Notes

Acknowledgments

We thank the University of Athens for support. The authors declare no competing financial interests. The authors sincerely thank the Editor-in-Chief for properly handling this manuscript and the anonymous reviewers for their very valuable and constructive criticism, which helped us to considerably improve the manuscript. This work was supported by computational time granted from the Greek Research & Technology Network (GRNET) in the National HPC facility—ARIS under project ID PR001025-M.D.S.B.M.S.

Supplementary material

10822_2015_9892_MOESM1_ESM.pdf (2.3 mb)
Supplementary material 1 (PDF 2381 kb)

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Nikolaos N. Louros
    • 1
  • Fotis A. Baltoumas
    • 1
  • Stavros J. Hamodrakas
    • 1
  • Vassiliki A. Iconomidou
    • 1
    Email author
  1. 1.Department of Cell Biology and Biophysics, Faculty of BiologyUniversity of AthensAthensGreece

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