TY - JOUR
T1 - A β-solenoid model of the Pmel17 repeat domain
T2 - Insights to the formation of functional amyloid fibrils
AU - Louros, Nikolaos N.
AU - Baltoumas, Fotis A.
AU - Hamodrakas, Stavros J.
AU - Iconomidou, Vassiliki A.
N1 - Publisher Copyright:
© 2016 Springer International Publishing Switzerland.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
KW - Amyloid fibrils
KW - Functional amyloid
KW - Homology modelling
KW - Molecular dynamics
KW - β-Helix
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U2 - 10.1007/s10822-015-9892-x
DO - 10.1007/s10822-015-9892-x
M3 - Article
C2 - 26754844
AN - SCOPUS:84954144396
SN - 0920-654X
VL - 30
SP - 153
EP - 164
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 2
ER -