TY - JOUR
T1 - Structural Properties of Neurofilament Sidearms
T2 - Sequence-Based Modeling of Neurofilament Architecture
AU - Chang, Rakwoo
AU - Kwak, Yongkyu
AU - Gebremichael, Yeshitila
PY - 2009/8/21
Y1 - 2009/8/21
N2 - Neurofilaments (NFs) are essential cytoskeletal filaments that impart mechanical integrity to nerve cells. They are assembled from three distinct molecular mass proteins that bind to each other to form a 10-nm-diameter filamentous rod with sidearm extensions. The sidearms are considered to play a critical role in modulating interfilament spacing and axonal caliber. However, the precise mechanism by which NF protrusions regulate axonal diameter remains to be well understood. In particular, the role played by individual NF protrusions in specifying interfilament distances is yet to be established. To gain insight into the role of individual proteins, we investigated the structural organization of NF architecture under different phosphorylation conditions. To this end, a physically motivated sequence-based coarse-grain model of NF brush has been developed based on the three-dimensional architecture of NFs. The model incorporates the charge distribution of sidearms, including charges from the phosphorylation sites corresponding to Lys-Ser-Pro repeat motifs. The model also incorporates the proper grafting of the real NF sidearms based on the stoichiometry of the three subunits. The equilibrium structure of the NF brush is then investigated under different phosphorylation conditions. The phosphorylation of NF modifies the structural organization of sidearms. Upon phosphorylation, a dramatic change involving a transformation from a compact conformation to an extended conformation is found in the heavy NF (NF-H) protein. However, in spite of extensive phosphorylation sites present in the NF-H subunit, the tails of the medium NF subunit are found to be more extended than the NF-H sidearms. This supports the notion that medium NF protrusions are critical in regulating NF spacings and, hence, axonal caliber.
AB - Neurofilaments (NFs) are essential cytoskeletal filaments that impart mechanical integrity to nerve cells. They are assembled from three distinct molecular mass proteins that bind to each other to form a 10-nm-diameter filamentous rod with sidearm extensions. The sidearms are considered to play a critical role in modulating interfilament spacing and axonal caliber. However, the precise mechanism by which NF protrusions regulate axonal diameter remains to be well understood. In particular, the role played by individual NF protrusions in specifying interfilament distances is yet to be established. To gain insight into the role of individual proteins, we investigated the structural organization of NF architecture under different phosphorylation conditions. To this end, a physically motivated sequence-based coarse-grain model of NF brush has been developed based on the three-dimensional architecture of NFs. The model incorporates the charge distribution of sidearms, including charges from the phosphorylation sites corresponding to Lys-Ser-Pro repeat motifs. The model also incorporates the proper grafting of the real NF sidearms based on the stoichiometry of the three subunits. The equilibrium structure of the NF brush is then investigated under different phosphorylation conditions. The phosphorylation of NF modifies the structural organization of sidearms. Upon phosphorylation, a dramatic change involving a transformation from a compact conformation to an extended conformation is found in the heavy NF (NF-H) protein. However, in spite of extensive phosphorylation sites present in the NF-H subunit, the tails of the medium NF subunit are found to be more extended than the NF-H sidearms. This supports the notion that medium NF protrusions are critical in regulating NF spacings and, hence, axonal caliber.
KW - Monte Carlo simulation
KW - neurofilament brush model
KW - neurofilament sidearms
KW - phosphorylation
KW - polyampholytes
UR - http://www.scopus.com/inward/record.url?scp=67651172762&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2009.06.045
DO - 10.1016/j.jmb.2009.06.045
M3 - Article
C2 - 19559031
AN - SCOPUS:67651172762
SN - 0022-2836
VL - 391
SP - 648
EP - 660
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 3
ER -